Ras Conformational Ensembles, Allostery, and Signaling

Chemical Reviews

Volumn 116, Issue 11, 2016, Pages 6607-6665

  Lu, Shaoyong ^a,b   Jang, Hyunbum ^b   Muratcioglu, Serena ^c   Gursoy, Attila ^c   Keskin, Ozlem ^c   Nussinov, Ruth ^b,d   Zhang, Jian ^a  

^a BEIJING UNIVERSITY OF POSTS AND TELECOMMUNICATIONS   (China)

^b FREDERICK NATIONAL LABORATORY FOR CANCER RESEARCH   (United States)

^c KOÇ UNIVERSITY   (Turkey)

^d TEL AVIV UNIVERSITY   (Israel)

Author keywords

[No Author keywords available]

Indexed keywords

CHEMICAL ACTIVATION; HYDROLYSIS;

ALLOSTERIC REGULATION; CONFORMATIONAL ENSEMBLE; GTPASE-ACTIVATING PROTEIN; GUANINE NUCLEOTIDE EXCHANGE FACTORS; MEMBRANE COMPOSITION; ORDERS OF MAGNITUDE; POST-TRANSLATIONAL MODIFICATIONS; THERAPEUTIC STRATEGY;

PROTEINS;

GUANOSINE TRIPHOSPHATE; PROTEIN BINDING; RAS PROTEIN;

ALLOSTERISM; CHEMISTRY; ENZYME ACTIVE SITE; METABOLISM; NUCLEAR MAGNETIC RESONANCE; PHYSIOLOGY; PROTEIN TERTIARY STRUCTURE; SIGNAL TRANSDUCTION;

ALLOSTERIC REGULATION; CATALYTIC DOMAIN; GUANOSINE TRIPHOSPHATE; NUCLEAR MAGNETIC RESONANCE, BIOMOLECULAR; PROTEIN BINDING; PROTEIN STRUCTURE, TERTIARY; RAS PROTEINS; SIGNAL TRANSDUCTION;

EID: 84957920707     PISSN: 00092665     EISSN: 15206890     Source Type: Journal    
DOI: 10.1021/acs.chemrev.5b00542     Document Type: Review

References (456)

1. Harvey, J. J. An Unidentified Virus Which Causes the Rapid Production of Tumours in Mice Nature 1964, 204, 1104-1105 10.1038/2041104b0
2. Chang, E. H.; Gonda, M. A.; Ellis, R. W.; Scolnick, E. M.; Lowy, D. R. Human Genome Contains Four Genes Homologous to Transforming Genes of Harvey and Kirsten Murine Sarcoma Viruses Proc. Natl. Acad. Sci. U. S. A. 1982, 79, 4848-4852 10.1073/pnas.79.16.4848
3. Wiesmüller, L.; Wittinghofer, F. Signal Transduction Pathways Involving Ras Cell. Signalling 1994, 6, 247-267 10.1016/0898-6568(94)90030-2
4. Bryant, K. L.; Mancias, J. D.; Kimmelman, A. C.; Der, C. J. KRAS: Feeding Pancreatic Cancer Proliferation Trends Biochem. Sci. 2014, 39, 91-100 10.1016/j.tibs.2013.12.004
5. Pylayeva-Gupta, Y.; Grabocka, E.; Bar-Sagi, D. RAS Oncogenes: Weaving a Tumorigenic Web Nat. Rev. Cancer 2011, 11, 761-774 10.1038/nrc3106
6. Cox, A. D.; Der, C. J. Ras History: The Saga Continues Small GTPases 2010, 1, 2-27 10.4161/sgtp.1.1.12178
7. Drosten, M.; Dhawahir, A.; Sum, E. Y. M.; Urosevic, J.; Lechuga, C. G.; Esteban, L. M.; Castellano, E.; Guerra, C.; Santos, E.; Barbacid, M. Genetic Analysis of Ras Signalling Pathways in Cell Proliferation, Migration and Survival EMBO J. 2010, 29, 1091-1104 10.1038/emboj.2010.7
8. Crespo, P.; León, J. Ras Proteins in the Control of the Cell Cycle and Cell Differentiation Cell. Mol. Life Sci. 2000, 57, 1613-1636 10.1007/PL00000645
9. ras GTPase-Activating Protein Mol. Cell. Biol. 1991, 11, 1804-1812 10.1128/MCB.11.4.1804
10. Holderfield, M.; Deuker, M. M.; McCormick, F.; McMahon, M. Targeting RAF Kinases for Cancer Therapy: BRAF-Mutated Melanoma and Beyond Nat. Rev. Cancer 2014, 14, 455-467 10.1038/nrc3760
11. Lavoie, H.; Thevakumaran, N.; Gavory, G.; Li, J. J.; Padeganeh, A.; Guiral, S.; Duchaine, J.; Mao, D. Y. L.; Bouvier, M.; Sicheri, F. et al. Inhibitors That Stabilize a Closed RAF Kinase Domain Conformation Induce Dimerization Nat. Chem. Biol. 2013, 9, 428-436 10.1038/nchembio.1257
12. De Luca, A.; Maiello, M. R.; D'Alessio, A.; Pergameno, M.; Normanno, N. The RAS/RAF/MEK/ERK and the PI3K/AKT Signalling Pathways: Role in Cancer Pathogenesis and Implications for Therapeutic Approaches Expert Opin. Ther. Targets 2012, 16, S17-S27 10.1517/14728222.2011.639361
13. Young, A.; Lou, D.; McCormick, F. Oncogenic and Wild-Type Ras Play Divergent Roles in the Regulation of Mitogen-Activated Protein Kinase Signaling Cancer Discovery 2013, 3, 112-123 10.1158/2159-8290.CD-12-0231
14. Nussinov, R.; Jang, H.; Tsai, C. The Structural Basis for Cancer Treatment Decisions Oncotarget 2014, 5, 7285-7302 10.18632/oncotarget.2439
15. Downward, J. Targeting RAS and PI3K in Lung Cancer Nat. Med. 2008, 14, 1315-1316 10.1038/nm1208-1315
16. Sheridan, C.; Downward, J. Inhibiting the RAS-PI3K Pathway in Cancer Therapy The Enzymes 2013, 34, 107-136 10.1016/B978-0-12-420146-0.00005-6
17. Cully, M.; Downward, J. SnapShot: Ras Signaling Cell 2008, 133, 1292-1292 10.1016/j.cell.2008.06.020
18. Downward, J. The Ras Superfamily of Small GTP-Binding Proteins Trends Biochem. Sci. 1990, 15, 469-472 10.1016/0968-0004(90)90300-Z
19. Grand, R. J.; Owen, D. The Biochemistry of Ras p21 Biochem. J. 1991, 279, 609-631 10.1042/bj2790609
20. Bourne, H. R.; Sanders, D. A.; McCormick, F. The GTPase Superfamily: Conserved Structure and Molecular Mechanism Nature 1991, 349, 117-127 10.1038/349117a0
21. Wittinghofer, A.; Pal, E. F. The Structure of Ras Protein: A Model for a Universal Molecular Switch Trends Biochem. Sci. 1991, 16, 382-387 10.1016/0968-0004(91)90156-P
22. ras Activity Trends Genet. 1991, 7, 346-351 10.1016/0168-9525(91)90253-M
23. Wittinghofer, A.; Vetter, I. R. Structure-Function Relationships of the G Domain, a Canonical Switch Motif Annu. Rev. Biochem. 2011, 80, 943-971 10.1146/annurev-biochem-062708-134043
24. Takai, Y.; Sasaki, T.; Matozaki, T. Small GTP-Binding Proteins Physiol. Rev. 2001, 81, 153-208
25. Lamontanara, A. J.; Georgeon, S.; Tria, G.; Svergun, D. I.; Hantschel, O. The SH2 Domain of Abl Kinases Regulates Kinase Autophosphorylation by Controlling Activation Loop Accessibility Nat. Commun. 2014, 5, 5470 10.1038/ncomms6470
26. Vetter, I. R.; Wittinghofer, A. The Guanine Nucleotide-Binding Switch in Three Dimensions Science 2001, 294, 1299-1304 10.1126/science.1062023
27. Cherfils, J.; Zeghouf, M. Regulation of Small GTPases by GEFs, GAPs, and GDIs Physiol. Rev. 2013, 93, 269-309 10.1152/physrev.00003.2012
28. Geyer, M.; Wittinghofer, A. GEFs, GAPs, GDIs and Effectors: Taking a Closer (3D) Look at the Regulation of Ras-Related GTP-Binding Proteins Curr. Opin. Struct. Biol. 1997, 7, 786-792 10.1016/S0959-440X(97)80147-9
29. Sprang, S. R. G Proteins, Effectors and GAPs: Structure and Mechanism Curr. Opin. Struct. Biol. 1997, 7, 849-856 10.1016/S0959-440X(97)80157-1
30. Wittinghofer, A.; Scheffzek, K.; Ahmadian, M. R. The Interaction of Ras with GTPase-Activating Proteins FEBS Lett. 1997, 410, 63-67 10.1016/S0014-5793(97)00321-9
31. Adjei, A. A. Blocking Oncogenic Ras Signaling for Cancer Therapy J. Natl. Cancer Inst. 2001, 93, 1062-1074 10.1093/jnci/93.14.1062
32. Vigil, D.; Cherfils, J.; Rossman, K. L.; Der, C. J. Ras Superfamily GEFs and GAPs: Validated and Tractable Targets for Cancer Therapy? Nat. Rev. Cancer 2010, 10, 842-857 10.1038/nrc2960
33. Schubbert, S.; Shannon, K.; Bollag, G. Hyperactive Ras in Developmental Disorders and Cancer Nat. Rev. Cancer 2007, 7, 295-308 10.1038/nrc2109
34. Smith, M. J.; Ikura, M. Integrated RAS Signaling Defined by Parallel NMR Detection of Effectors and Regulators Nat. Chem. Biol. 2014, 10, 223-230 10.1038/nchembio.1435
35. Smith, M. J.; Neel, B. G.; Ikura, M. NMR-Based Functional Profiling of RASopathies and Oncogenic RAS Mutations Proc. Natl. Acad. Sci. U. S. A. 2013, 110, 4574-4579 10.1073/pnas.1218173110
36. Eser, S.; Schnieke, A.; Schneider, G.; Saur, D. Oncogenic KRAS Signalling in Pancreatic Cancer Br. J. Cancer 2014, 111, 817-822 10.1038/bjc.2014.215
37. Prior, I. A.; Lewis, P. D.; Mattos, C. A Comprehensive Survey of Ras Mutations in Cancer Cancer Res. 2012, 72, 2457-2467 10.1158/0008-5472.CAN-11-2612
38. Stephen, A. G.; Esposito, D.; Bagni, R. K.; McCormick, F. Dragging Ras Back in the Ring Cancer Cell 2014, 25, 272-281 10.1016/j.ccr.2014.02.017
39. McCormick, F. KRAS as a Therapeutic Target Clin. Cancer Res. 2015, 21, 1797-1801 10.1158/1078-0432.CCR-14-2662
40. McCormick, F. The Potential of Targeting Ras Proteins in Lung Cancer Expert Opin. Ther. Targets 2015, 19, 451-454 10.1517/14728222.2014.1000304
41. Chen, L.; Tao, Y.; Jiang, Y. Apelin Activates the Expression of Inflammatory Cytokines in Microglial BV2 Cells via PI-3K/Akt and MEK/Erk Pathways Sci. China: Life Sci. 2015, 58, 531-540 10.1007/s11427-015-4861-0
42. Krens, L. L.; Baas, J. M.; Gelderblom, H.; Guchelaar, H.-J. Therapeutic Modulation of K-Ras Signaling in Colorectal Cancer Drug Discovery Today 2010, 15, 502-516 10.1016/j.drudis.2010.05.012
43. Cox, A. D.; Fesik, S. W.; Kimmelman, A. C.; Luo, J.; Der, C. J. Drugging the Undruggable RAS: Mission Possible? Nat. Rev. Drug Discovery 2014, 13, 828-851 10.1038/nrd4389
44. Ledford, H. Cancer: The Ras Renaissance Nature 2015, 520, 278-280 10.1038/520278a
45. Milroy, L.; Ottmann, C. The Renaissance of Ras ACS Chem. Biol. 2014, 9, 2447-2458 10.1021/cb500555h
46. Samatar, A. A.; Poulikakos, P. I. Targeting RAS-ERK Signalling in Cancer: Promises and Challenges Nat. Rev. Drug Discovery 2014, 13, 928-942 10.1038/nrd4281
47. Wang, Y.; Kaiser, C. E.; Frett, B.; Li, H. Targeting Mutant KRAS for Anticancer Therapeutics: A Review of Novel Small Molecule Modulators J. Med. Chem. 2013, 56, 5219-5230 10.1021/jm3017706
48. Spiegel, J.; Cromm, P. M.; Zimmermann, G.; Grossmann, T. N.; Waldmann, H. Small-Molecule Modulation of Ras Signaling Nat. Chem. Biol. 2014, 10, 613-622 10.1038/nchembio.1560
49. Zimmermann, G.; Papke, B.; Ismail, S.; Vartak, N.; Chandra, A.; Hoffmann, M.; Hahn, S. A.; Triola, G.; Wittinghofer, A.; Bastiaens, P. I. H. et al. Small Molecule Inhibition of the KRAS-PDE Interaction Impairs Oncogenic KRAS Signalling Nature 2013, 497, 638-642 10.1038/nature12205
50. McCormick, F. Success and Failure on the Ras Pathway Cancer Biol. Ther. 2007, 6, 1654-1659 10.4161/cbt.6.10.5153
51. Gysin, S.; Salt, M.; Young, A.; McCormick, F. Therapeutic Strategies for Targeting Ras Proteins Genes Cancer 2011, 2, 359-372 10.1177/1947601911412376
52. Shao, T.; Zheng, Y.; Zhao, B.; Li, T.; Cheng, K.; Cai, W. Recombinant Expression of Different Mutant K-Ras Gene in Pancreatic Cancer Bxpc-3 Cells and Its Effects on Chemotherapy Sensitivity Sci. China: Life Sci. 2014, 57, 1011-1017 10.1007/s11427-014-4724-0
53. Stites, E. C.; Ravichandran, K. S. A Systems Perspective of Ras Signaling in Cancer Clin. Cancer Res. 2009, 15, 1510-1513 10.1158/1078-0432.CCR-08-2753
54. Lu, S.; Jang, H.; Zhang, J.; Nussinov, R. Inhibitors of Ras-SOS Interactions ChemMedChem 2015, 10.1002/cmdc.201500481
55. Thompson, H. US National Cancer Institute's New Ras Project Targets an Old Foe Nat. Med. 2013, 19, 949-950 10.1038/nm0813-949
56. Bollag, G.; Zhang, C. Drug Discovery: Pocket of Opportunity Nature 2013, 503, 475-476 10.1038/nature12835
57. Seton-Rogers, S. Oncogenes: Direct Hit on Mutant RAS Nat. Rev. Cancer 2014, 14, 8-9 10.1038/nrc3650
58. Fanelli, F.; Raimondi, F. Nucleotide Binding Affects Intrinsic Dynamics and Structural Communication in Ras GTPases Curr. Pharm. Des. 2013, 19, 4214-4225 10.2174/1381612811319230006
59. Sun, Q.; Phan, J.; Friberg, A. R.; Camper, D. V.; Olejniczak, E. T.; Fesik, S. W. A Method for the Second-Site Screening of K-Ras in the Presence of a Covalently Attached First-Site Ligand J. Biomol. NMR 2014, 60, 11-14 10.1007/s10858-014-9849-8
60. Long, D.; Marshall, C. B.; Bouvignies, G.; Mazhab-Jafari, M. T.; Smith, M. J.; Ikura, M.; Kay, L. E. A Comparative CEST NMR Study of Slow Conformational Dynamics of Small GTPases Complexed with GTP and GTP Analogues Angew. Chem.; Int. Ed. 2013, 52, 10771-10774 10.1002/anie.201305434
61. Prakash, P.; Hancock, J. F.; Gorfe, A. A. Binding Hotspots on K-Ras: Consensus Ligand Binding Sites and Other Reactive Regions from Probe-Based Molecular Dynamics Analysis Proteins: Struct.; Funct.; Genet. 2015, 83, 898-909 10.1002/prot.24786
62. Prakash, P.; Sayyed-Ahmad, A.; Gorfe, A. A. The Role of Conserved Waters in Conformational Transitions of Q61H K-Ras PLoS Comput. Biol. 2012, 8, e1002394 10.1371/journal.pcbi.1002394
63. Grant, B. J.; Lukman, S.; Hocker, H. J.; Sayyah, J.; Brown, J. H.; McCammon, J. A.; Gorfe, A. A. Novel Allosteric Sites on Ras for Lead Generation PLoS One 2011, 6, e25711 10.1371/journal.pone.0025711
64. Marcus, K.; Mattos, C. Direct Attack on RAS: Intramolecular Communication and Mutation-Specific Effects Clin. Cancer Res. 2015, 21, 1810-1818 10.1158/1078-0432.CCR-14-2148
65. Buhrman, G.; Kumar, V. S. S.; Cirit, M.; Haugh, J. M.; Mattos, C. Allosteric Modulation of Ras-GTP Is Linked to Signal Transduction through RAF Kinase J. Biol. Chem. 2011, 286, 3323-3331 10.1074/jbc.M110.193854
66. Kearney, B. M.; Johnson, C. W.; Roberts, D. M.; Swartz, P.; Mattos, C. DRoP: A Water Analysis Program Identifies Ras-GTP-Specific Pathway of Communication between Membrane-Interacting Regions and the Active Site J. Mol. Biol. 2014, 426, 611-629 10.1016/j.jmb.2013.10.036
67. Johnson, C. W.; Mattos, C. The Allosteric Switch and Conformational States in Ras GTPase Affected by Small Molecules Enzym. 2013, 33, 41-67 10.1016/B978-0-12-416749-0.00003-8
68. Ye, M.; Shima, F.; Muraoka, S.; Liao, J.; Okamoto, H.; Yamamoto, M.; Tamura, A.; Yagi, N.; Ueki, T.; Kataoka, T. Crystal Structure of M-Ras Reveals a GTP-Bound "off" State Conformation of Ras Family Small GTPases J. Biol. Chem. 2005, 280, 31267-31275 10.1074/jbc.M505503200
69. 31P NMR Spectroscopy Magn. Reson. Chem. 2005, 43, S74-S83 10.1002/mrc.1693
70. Shima, F.; Yoshikawa, Y.; Ye, M.; Araki, M.; Matsumoto, S.; Liao, J.; Hu, L.; Sugimoto, T.; Ijiri, Y.; Takeda, A. et al. In Silico Discovery of Small-Molecule Ras Inhibitors That Display Antitumor Activity by Blocking the Ras-Effector Interaction Proc. Natl. Acad. Sci. U. S. A. 2013, 110, 8182-8187 10.1073/pnas.1217730110
71. Lim, S. M.; Westover, K. D.; Ficarro, S. B.; Harrison, R. A.; Choi, H. G.; Pacold, M. E.; Carrasco, M.; Hunter, J.; Kim, N. D.; Xie, T. et al. Therapeutic Targeting of Oncogenic K-Ras by a Covalent Catalytic Site Inhibitor Angew. Chem.; Int. Ed. 2014, 53, 199-204 10.1002/anie.201307387
72. Hunter, J. C.; Gurbani, D.; Ficarro, S. B.; Carrasco, M. a; Lim, S. M.; Choi, H. G.; Xie, T.; Marto, J. A.; Chen, Z.; Gray, N. S. et al. In Situ Selectivity Profiling and Crystal Structure of SML-8-73-1, an Active Site Inhibitor of Oncogenic K-Ras G12C Proc. Natl. Acad. Sci. U. S. A. 2014, 111, 8895-8900 10.1073/pnas.1404639111
73. Ostrem, J. M.; Peters, U.; Sos, M. L.; Wells, J. A.; Shokat, K. M. K-Ras(G12C) Inhibitors Allosterically Control GTP Affinity and Effector Interactions Nature 2013, 503, 548-551 10.1038/nature12796
74. Nussinov, R.; Wolynes, P. G. A Second Molecular Biology Revolution? The Energy Landscapes of Biomolecular Function Phys. Chem. Chem. Phys. 2014, 16, 6321-6322 10.1039/c4cp90027h
75. Frauenfelder, H.; Sligar, S. G.; Wolynes, P. G. The Energy Landscapes and Motions of Proteins Science 1991, 254, 1598-1603 10.1126/science.1749933
76. Kumar, S.; Ma, B.; Tsai, C. J.; Sinha, N.; Nussinov, R. Folding and Binding Cascades: Dynamic Landscapes and Population Shifts Protein Sci. 2000, 9, 10-19 10.1110/ps.9.1.10
77. Ma, B.; Shatsky, M.; Wolfson, H. J.; Nussinov, R. Multiple Diverse Ligands Binding at a Single Protein Site: A Matter of Pre-Existing Populations Protein Sci. 2002, 11, 184-197 10.1110/ps.21302
78. Tsai, C. J.; Ma, B.; Nussinov, R. Folding and Binding Cascades: Shifts in Energy Landscapes Proc. Natl. Acad. Sci. U. S. A. 1999, 96, 9970-9972 10.1073/pnas.96.18.9970
79. Tsai, C. J.; Kumar, S.; Ma, B.; Nussinov, R. Folding Funnels, Binding Funnels, and Protein Function Protein Sci. 1999, 8, 1181-1190 10.1110/ps.8.6.1181
80. Tsai, C.-J.; Nussinov, R. The Free Energy Landscape in Translational Science: How Can Somatic Mutations Result in Constitutive Oncogenic Activation? Phys. Chem. Chem. Phys. 2014, 16, 6332-6341 10.1039/c3cp54253j
81. Nussinov, R.; Tsai, C.-J. Unraveling Structural Mechanisms of Allosteric Drug Action Trends Pharmacol. Sci. 2014, 35, 256-264 10.1016/j.tips.2014.03.006
82. Kar, G.; Keskin, O.; Gursoy, A.; Nussinov, R. Allostery and Population Shift in Drug Discovery Curr. Opin. Pharmacol. 2010, 10, 715-722 10.1016/j.coph.2010.09.002
83. Nussinov, R.; Ma, B. Protein Dynamics and Conformational Selection in Bidirectional Signal Transduction BMC Biol. 2012, 10, 2 10.1186/1741-7007-10-2
84. Boehr, D. D.; Nussinov, R.; Wright, P. E. The Role of Dynamic Conformational Ensembles in Biomolecular Recognition Nat. Chem. Biol. 2009, 5, 789-796 10.1038/nchembio.232
85. Mackereth, C. D.; Madl, T.; Bonnal, S.; Simon, B.; Zanier, K.; Gasch, A.; Rybin, V.; Valcárcel, J.; Sattler, M. Multi-Domain Conformational Selection Underlies Pre-mRNA Splicing Regulation by U2AF Nature 2011, 475, 408-411 10.1038/nature10171
86. Motlagh, H. N.; Wrabl, J. O.; Li, J.; Hilser, V. J. The Ensemble Nature of Allostery Nature 2014, 508, 331-339 10.1038/nature13001
87. Okazaki, K.; Takada, S. Dynamic Energy Landscape View of Coupled Binding and Protein Conformational Change: Induced-Fit versus Population-Shift Mechanisms Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 11182-11187 10.1073/pnas.0802524105
88. Arora, K.; Brooks, C. L. Large-Scale Allosteric Conformational Transitions of Adenylate Kinase Appear to Involve a Population-Shift Mechanism Proc. Natl. Acad. Sci. U. S. A. 2007, 104, 18496-18501 10.1073/pnas.0706443104
89. Huang, W.; Wang, G.; Shen, Q.; Liu, X.; Lu, S.; Geng, L.; Huang, Z.; Zhang, J. ASBench: Benchmarking Sets for Allosteric Discovery Bioinformatics 2015, 31, 2598-2600 10.1093/bioinformatics/btv169
90. Barbacid, M. Ras Genes Annu. Rev. Biochem. 1987, 56, 779-827 10.1146/annurev.bi.56.070187.004023
91. Malumbres, M.; Barbacid, M. RAS Oncogenes: The First 30 Years Nat. Rev. Cancer 2003, 3, 459-465 10.1038/nrc1097
92. Cox, A. D.; Der, C. J.; Philips, M. R. Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery? Clin. Cancer Res. 2015, 21, 1819-1827 10.1158/1078-0432.CCR-14-3214
93. Nussinov, R.; Tsai, C.-J.; Chakrabarti, M.; Jang, H. A New View of Ras Isoforms in Cancers Cancer Res. 2016, 76, 18-23 10.1158/0008-5472.CAN-15-1536
94. Castellano, E.; Santos, E. Functional Specificity of Ras Isoforms: So Similar but so Different Genes Cancer 2011, 2, 216-231 10.1177/1947601911408081
95. Quinlan, M. P.; Settleman, J. Isoform-Specific Ras Functions in Development and Cancer Future Oncol. 2009, 5, 105-116 10.2217/14796694.5.1.105
96. Ellis, C. A.; Clark, G. The Importance of Being K-Ras Cell. Signalling 2000, 12, 425-434 10.1016/S0898-6568(00)00084-X
97. Forbes, S. A.; Bindal, N.; Bamford, S.; Cole, C.; Kok, C. Y.; Beare, D.; Jia, M.; Shepherd, R.; Leung, K.; Menzies, A. et al. COSMIC: Mining Complete Cancer Genomes in the Catalogue of Somatic Mutations in Cancer Nucleic Acids Res. 2011, 39, D945-D950 10.1093/nar/gkq929
98. Karnoub, A. E.; Weinberg, R. A. Ras Oncogenes: Split Personalities Nat. Rev. Mol. Cell Biol. 2008, 9, 517-531 10.1038/nrm2438
99. Orita, S.; Higashi, T.; Kawasaki, Y.; Harada, A.; Igarashi, H.; Monden, T.; Morimoto, H.; Shimano, T.; Mori, T.; Miyoshi, J. A Novel Point Mutation at Codon 146 of the K-Ras Gene in a Human Colorectal Cancer Identified by the Polymerase Chain Reaction Virus Genes 1991, 5, 75-79 10.1007/BF00571733
100. Akagi, K.; Uchibori, R.; Yamaguchi, K.; Kurosawa, K.; Tanaka, Y.; Kozu, T. Characterization of a Novel Oncogenic K-Ras Mutation in Colon Cancer Biochem. Biophys. Res. Commun. 2007, 352, 728-732 10.1016/j.bbrc.2006.11.091
101. Smith, G.; Bounds, R.; Wolf, H.; Steele, R. J. C.; Carey, F. A.; Wolf, C. R. Activating K-Ras Mutations Outwith "Hotspot" Codons in Sporadic Colorectal Tumours-Implications for Personalised Cancer Medicine Br. J. Cancer 2010, 102, 693-703 10.1038/sj.bjc.6605534
102. Bernard, V.; Gebauer, N.; Dinh, T.; Stegemann, J.; Feller, A. C.; Merz, H. Applicability of next-Generation Sequencing to Decalcified Formalin-Fixed and Paraffin-Embedded Chronic Myelomonocytic Leukaemia Samples Int. J. Clin. Exp. Pathol. 2014, 7, 1667-1676
103. Colicelli, J. Human RAS Superfamily Proteins and Related GTPases Sci. Signaling 2004, 2004, re13 10.1126/stke.2502004re13
104. Nussinov, R.; Tsai, C.-J.; Mattos, C. Pathway Drug Cocktail": Targeting Ras Signaling Based on Structural Pathways Trends Mol. Med. 2013, 19, 695-704 10.1016/j.molmed.2013.07.009
105. Downward, J. RAS's Cloak of Invincibility Slips at Last? Cancer Cell 2014, 25, 5-6 10.1016/j.ccr.2013.12.016
106. Kiel, C.; Serrano, L. Structure-Energy-Based Predictions and Network Modelling of RASopathy and Cancer Missense Mutations Mol. Syst. Biol. 2014, 10, 727 10.1002/msb.20145092
107. Nussinov, R.; Jang, H.; Tsai, C.-J. Oligomerization and Nanocluster Organization Render Specificity Biol. Rev. 2015, 90, 587-598 10.1111/brv.12124
108. Long, S. B.; Casey, P. J.; Beese, L. S. The Basis for K-Ras4B Binding Specificity to Protein Farnesyltransferase Revealed by 2 Å Resolution Ternary Complex Structures Structure 2000, 8, 209-222 10.1016/S0969-2126(00)00096-4
109. Reid, T. S.; Terry, K. L.; Casey, P. J.; Beese, L. S. Crystallographic Analysis of CaaX Prenyltransferases Complexed with Substrates Defines Rules of Protein Substrate Selectivity J. Mol. Biol. 2004, 343, 417-433 10.1016/j.jmb.2004.08.056
110. Newman, C. M.; Magee, A. I. Posttranslational Processing of the Ras Superfamily of Small GTP-Binding Proteins Biochim. Biophys. Acta, Rev. Cancer 1993, 1155, 79-96 10.1016/0304-419X(93)90023-6
111. Downward, J. Targeting RAS Signalling Pathways in Cancer Therapy Nat. Rev. Cancer 2003, 3, 11-22 10.1038/nrc969
112. Buday, L.; Downward, J. Many Faces of Ras Activation Biochim. Biophys. Acta, Rev. Cancer 2008, 1786, 178-187 10.1016/j.bbcan.2008.05.001
113. Shields, J. M.; Pruitt, K.; McFall, A.; Shaub, A.; Der, C. J. Understanding Ras: "It Ain't over Til It's Over" Trends Cell Biol. 2000, 10, 147-154 10.1016/S0962-8924(00)01740-2
114. Willumsen, B. M.; Christensen, A.; Hubbert, N. L.; Papageorge, A. G.; Lowy, D. R. The p21 Ras C-Terminus Is Required for Transformation and Membrane Association Nature 1984, 310, 583-586 10.1038/310583a0
115. Wright, L. P.; Philips, M. R. Thematic Review Series: Lipid Posttranslational Modifications. CAAX Modification and Membrane Targeting of Ras J. Lipid Res. 2006, 47, 883-891 10.1194/jlr.R600004-JLR200
116. Chiu, V. K.; Silletti, J.; Dinsell, V.; Wiener, H.; Loukeris, K.; Ou, G.; Philips, M. R.; Pillinger, M. H. Carboxyl Methylation of Ras Regulates Membrane Targeting and Effector Engagement J. Biol. Chem. 2004, 279, 7346-7352 10.1074/jbc.M311602200
117. Laude, A. J.; Prior, I. A. Palmitoylation and Localisation of RAS Isoforms Are Modulated by the Hypervariable Linker Domain J. Cell Sci. 2008, 121, 421-427 10.1242/jcs.020107
118. Roy, S.; Plowman, S.; Rotblat, B.; Prior, I. A.; Muncke, C.; Grainger, S.; Parton, R. G.; Henis, Y. I.; Kloog, Y.; Hancock, J. F. Individual Palmitoyl Residues Serve Distinct Roles in H-Ras: Trafficking, Microlocalization, and Signaling Mol. Cell. Biol. 2005, 25, 6722-6733 10.1128/MCB.25.15.6722-6733.2005
119. Yang, M. H.; Nickerson, S.; Kim, E. T.; Liot, C.; Laurent, G.; Spang, R.; Philips, M. R.; Shan, Y.; Shaw, D. E.; Bar-Sagi, D. et al. Regulation of RAS Oncogenicity by Acetylation Proc. Natl. Acad. Sci. U. S. A. 2012, 109, 10843-10848 10.1073/pnas.1201487109
120. Ahearn, I. M.; Haigis, K.; Bar-Sagi, D.; Philips, M. R. Regulating the Regulator: Post-Translational Modification of RAS Nat. Rev. Mol. Cell Biol. 2012, 13, 39-51 10.1038/nrm3255
121. Jura, N.; Scotto-Lavino, E.; Sobczyk, A.; Bar-Sagi, D. Differential Modification of Ras Proteins by Ubiquitination Mol. Cell 2006, 21, 679-687 10.1016/j.molcel.2006.02.011
122. Mott, H. R.; Carpenter, J. W.; Campbell, S. L. Structural and Functional Analysis of a Mutant Ras Protein That Is Insensitive to Nitric Oxide Activation Biochemistry 1997, 36, 3640-3644 10.1021/bi962790o
123. Baker, R.; Lewis, S. M.; Sasaki, A. T.; Wilkerson, E. M.; Locasale, J. W.; Cantley, L. C.; Kuhlman, B.; Dohlman, H. G.; Campbell, S. L. Site-Specific Monoubiquitination Activates Ras by Impeding GTPase-Activating Protein Function Nat. Struct. Mol. Biol. 2013, 20, 46-52 10.1038/nsmb.2430
124. Herrmann, C.; Ahmadian, M. R.; Hofmann, F.; Just, I. Functional Consequences of Monoglucosylation of Ha-Ras at Effector Domain Amino Acid Threonine 35 J. Biol. Chem. 1998, 273, 16134-16139 10.1074/jbc.273.26.16134
125. Hobbs, G. A.; Bonini, M. G.; Gunawardena, H. P.; Chen, X.; Campbell, S. L. Glutathiolated Ras: Characterization and Implications for Ras Activation Free Radical Biol. Med. 2013, 57, 221-229 10.1016/j.freeradbiomed.2012.10.531
126. Vetter, I. R.; Hofmann, F.; Wohlgemuth, S.; Herrmann, C.; Just, I. Structural Consequences of Mono-Glucosylation of Ha-Ras by Clostridium Sordellii Lethal Toxin J. Mol. Biol. 2000, 301, 1091-1095 10.1006/jmbi.2000.4045
127. Sasaki, A. T.; Carracedo, A.; Locasale, J. W.; Anastasiou, D.; Takeuchi, K.; Kahoud, E. R.; Haviv, S.; Asara, J. M.; Pandolfi, P. P.; Cantley, L. C. Ubiquitination of K-Ras Enhances Activation and Facilitates Binding to Select Downstream Effectors Sci. Signaling 2011, 4, ra13 10.1126/scisignal.2001518
128. Brunsveld, L.; Waldmann, H.; Huster, D. Membrane Binding of Lipidated Ras Peptides and Proteins - the Structural Point of View Biochim. Biophys. Acta, Biomembr. 2009, 1788, 273-288 10.1016/j.bbamem.2008.08.006
129. Jang, H.; Abraham, S. J.; Chavan, T. S.; Hitchinson, B.; Khavrutskii, L.; Tarasova, N. I.; Nussinov, R.; Gaponenko, V. Mechanisms of Membrane Binding of Small GTPase K-Ras4B Farnesylated Hypervariable Region J. Biol. Chem. 2015, 290, 9465-9477 10.1074/jbc.M114.620724
130. Roy, S.; Luetterforst, R.; Harding, A.; Apolloni, A.; Etheridge, M.; Stang, E.; Rolls, B.; Hancock, J. F.; Parton, R. G. Dominant-Negative Caveolin Inhibits H-Ras Function by Disrupting Cholesterol-Rich Plasma Membrane Domains Nat. Cell Biol. 1999, 1, 98-105 10.1038/10067
131. Philips, M. R. Ras Hitchhikes on PDE6 Nat. Cell Biol. 2012, 14, 128-129 10.1038/ncb2429
132. Arozarena, I.; Calvo, F.; Crespo, P. Ras, an Actor on Many Stages: Posttranslational Modifications, Localization, and Site-Specified Events Genes Cancer 2011, 2, 182-194 10.1177/1947601911409213
133. Chiu, V. K.; Bivona, T.; Hach, A.; Sajous, J. B.; Silletti, J.; Wiener, H.; Johnson, R. L.; Cox, A. D.; Philips, M. R. Ras Signalling on the Endoplasmic Reticulum and the Golgi Nat. Cell Biol. 2002, 4, 343-350 10.1038/ncb783
134. Schmick, M.; Vartak, N.; Papke, B.; Kovacevic, M.; Truxius, D. C.; Rossmannek, L.; Bastiaens, P. I. H. KRas Localizes to the Plasma Membrane by Spatial Cycles of Solubilization, Trapping and Vesicular Transport Cell 2014, 157, 459-471 10.1016/j.cell.2014.02.051
135. Bivona, T. G.; Philips, M. R. Ras Pathway Signaling on Endomembranes Curr. Opin. Cell Biol. 2003, 15, 136-142 10.1016/S0955-0674(03)00016-4
136. Quatela, S. E.; Philips, M. R. Ras Signaling on the Golgi Curr. Opin. Cell Biol. 2006, 18, 162-167 10.1016/j.ceb.2006.02.004
137. Schmick, M.; Kraemer, A.; Bastiaens, P. I. H. Ras Moves to Stay in Place Trends Cell Biol. 2015, 25, 190-197 10.1016/j.tcb.2015.02.004
138. Hancock, J. F. Ras Proteins: Different Signals from Different Locations Nat. Rev. Mol. Cell Biol. 2003, 4, 373-384 10.1038/nrm1105
139. Fehrenbacher, N.; Bar-Sagi, D.; Philips, M. Ras/MAPK Signaling from Endomembranes Mol. Oncol. 2009, 3, 297-307 10.1016/j.molonc.2009.06.004
140. Choy, E.; Chiu, V. K.; Silletti, J.; Feoktistov, M.; Morimoto, T.; Michaelson, D.; Ivanov, I. E.; Philips, M. R. Endomembrane Trafficking of Ras: The CAAX Motif Targets Proteins to the ER and Golgi Cell 1999, 98, 69-80 10.1016/S0092-8674(00)80607-8
141. Plowman, S. J.; Hancock, J. F. Ras Signaling from Plasma Membrane and Endomembrane Microdomains Biochim. Biophys. Acta, Mol. Cell Res. 2005, 1746, 274-283 10.1016/j.bbamcr.2005.06.004
142. Lynch, S. J.; Snitkin, H.; Gumper, I.; Philips, M. R.; Sabatini, D.; Pellicer, A. The Differential Palmitoylation States of N-Ras and H-Ras Determine Their Distinct Golgi Subcompartment Localizations J. Cell. Physiol. 2015, 230, 610-619 10.1002/jcp.24779
143. De Vos, A. M.; Tong, L.; Milburn, M. V.; Matias, P. M.; Jancarik, J.; Noguchi, S.; Nishimura, S.; Miura, K.; Ohtsuka, E.; Kim, S. H. Three-Dimensional Structure of an Oncogene Protein: Catalytic Domain of Human c-H-Ras p21 Science 1988, 239, 888-893 10.1126/science.2448879
144. Krengel, U.; Schlichting, I.; Scherer, A.; Schumann, R.; Frech, M.; John, J.; Kabsch, W.; Pai, E. F.; Wittinghofer, A. Three-Dimensional Structures of H-Ras p21 Mutants: Molecular Basis for Their Inability to Function as Signal Switch Molecules Cell 1990, 62, 539-548 10.1016/0092-8674(90)90018-A
145. Pai, E. F.; Krengel, U.; Petsko, G. A.; Goody, R. S.; Kabsch, W.; Wittinghofer, A. Refined Crystal Structure of the Triphosphate Conformation of H-Ras p21 at 1.35 Å Resolution: Implications for the Mechanism of GTP Hydrolysis EMBO J. 1990, 9, 2351-2359
146. Milburn, M. V.; Tong, L.; DeVos, A. M.; Brünger, A.; Yamaizumi, Z.; Nishimura, S.; Kim, S. H. Molecular Switch for Signal Transduction: Structural Differences between Active and Inactive Forms of Protooncogenic Ras Proteins Science 1990, 247, 939-945 10.1126/science.2406906
147. Ahmadian, M. R.; Zor, T.; Vogt, D.; Kabsch, W.; Selinger, Z.; Wittinghofer, A.; Scheffzek, K. Guanosine Triphosphatase Stimulation of Oncogenic Ras Mutants Proc. Natl. Acad. Sci. U. S. A. 1999, 96, 7065-7070 10.1073/pnas.96.12.7065
148. Franken, S. M.; Scheidig, A. J.; Krengel, U.; Rensland, H.; Lautwein, A.; Geyer, M.; Scheffzek, K.; Goody, R. S.; Kalbitzer, H. R.; Pai, E. F.; Wittinghofer, A. Three-Dimensional Structures and Properties of a Transforming and a Nontransforming Glycine-12 Mutant of p21H-Ras Biochemistry 1993, 32, 8411-8420 10.1021/bi00084a005
149. Tong, L. A.; de Vos, A. M.; Milburn, M. V.; Jancarik, J.; Noguchi, S.; Nishimura, S.; Miura, K.; Ohtsuka, E.; Kim, S. H. Structural Differences between a Ras Oncogene Protein and the Normal Protein Nature 1989, 337, 90-93 10.1038/337090a0
150. Tong, L. A.; de Vos, A. M.; Milburn, M. V.; Kim, S. H. Crystal Structures at 2.2 Å Resolution of the Catalytic Domains of Normal Ras Protein and an Oncogenic Mutant Complexed with GDP J. Mol. Biol. 1991, 217, 503-516 10.1016/0022-2836(91)90753-S
151. Hunter, J. C.; Manandhar, A.; Carrasco, M. A.; Gurbani, D.; Gondi, S.; Westover, K. D. Biochemical and Structural Analysis of Common Cancer-Associated KRAS Mutations Mol. Cancer Res. 2015, 13, 1325-1335 10.1158/1541-7786.MCR-15-0203
152. Nassar, N.; Singh, K.; Garcia-Diaz, M. Structure of the Dominant Negative S17N Mutant of Ras Biochemistry 2010, 49, 1970-1974 10.1021/bi9020742
153. Shima, F.; Ijiri, Y.; Muraoka, S.; Liao, J.; Ye, M.; Araki, M.; Matsumoto, K.; Yamamoto, N.; Sugimoto, T.; Yoshikawa, Y. et al. Structural Basis for Conformational Dynamics of GTP-Bound Ras Protein J. Biol. Chem. 2010, 285, 22696-22705 10.1074/jbc.M110.125161
154. Cirstea, I. C.; Kutsche, K.; Dvorsky, R.; Gremer, L.; Carta, C.; Horn, D.; Roberts, A. E.; Lepri, F.; Merbitz-Zahradnik, T.; König, R. et al. A Restricted Spectrum of NRAS Mutations Causes Noonan Syndrome Nat. Genet. 2010, 42, 27-29 10.1038/ng.497
155. Hall, B. E.; Bar-Sagi, D.; Nassar, N. The Structural Basis for the Transition from Ras-GTP to Ras-GDP Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 12138-12142 10.1073/pnas.192453199
156. Privé, G. G.; Milburn, M. V.; Tong, L.; de Vos, A. M.; Yamaizumi, Z.; Nishimura, S.; Kim, S. H. X-Ray Crystal Structures of Transforming p21 Ras Mutants Suggest a Transition-State Stabilization Mechanism for GTP Hydrolysis Proc. Natl. Acad. Sci. U. S. A. 1992, 89, 3649-3653 10.1073/pnas.89.8.3649
157. Ford, B.; Skowronek, K.; Boykevisch, S.; Bar-Sagi, D.; Nassar, N. Structure of the G60A Mutant of Ras: Implications for the Dominant Negative Effect J. Biol. Chem. 2005, 280, 25697-25705 10.1074/jbc.M502240200
158. Buhrman, G.; Wink, G.; Mattos, C. Transformation Efficiency of RasQ61 Mutants Linked to Structural Features of the Switch Regions in the Presence of Raf Structure 2007, 15, 1618-1629 10.1016/j.str.2007.10.011
159. Denayer, E.; Parret, A.; Chmara, M.; Schubbert, S.; Vogels, A.; Devriendt, K.; Frijns, J.; Rybin, V.; de Ravel, T. J.; Shannon, K. et al. Mutation Analysis in Costello Syndrome: Functional and Structural Characterization of the HRAS p.Lys117Arg Mutation Hum. Mutat. 2008, 29, 232-239 10.1002/humu.20616
160. Ting, P. Y.; Johnson, C. W.; Fang, C.; Cao, X.; Graeber, T. G.; Mattos, C.; Colicelli, J. Tyrosine Phosphorylation of RAS by ABL Allosterically Enhances Effector Binding FASEB J. 2015, 29, 3750-3761 10.1096/fj.15-271510
161. Ford, B.; Boykevisch, S.; Zhao, C.; Kunzelmann, S.; Bar-Sagi, D.; Herrmann, C.; Nassar, N. Characterization of a Ras Mutant with Identical GDP- and GTP-Bound Structures Biochemistry 2009, 48, 11449-11457 10.1021/bi901479b
162. Fetics, S. K.; Guterres, H.; Kearney, B. M.; Buhrman, G.; Ma, B.; Nussinov, R.; Mattos, C. Allosteric Effects of the Oncogenic RasQ61L Mutant on Raf-RBD Structure 2015, 23, 505-516 10.1016/j.str.2014.12.017
163. Pacold, M. E.; Suire, S.; Perisic, O.; Lara-Gonzalez, S.; Davis, C. T.; Walker, E. H.; Hawkins, P. T.; Stephens, L.; Eccleston, J. F.; Williams, R. L. Crystal Structure and Functional Analysis of Ras Binding to Its Effector Phosphoinositide 3-Kinase Gamma Cell 2000, 103, 931-943 10.1016/S0092-8674(00)00196-3
164. Huang, L.; Hofer, F.; Martin, G. S.; Kim, S. H. Structural Basis for the Interaction of Ras with RalGDS Nat. Struct. Biol. 1998, 5, 422-426 10.1038/nsb0698-422
165. Stieglitz, B.; Bee, C.; Schwarz, D.; Yildiz, O.; Moshnikova, A.; Khokhlatchev, A.; Herrmann, C. Novel Type of Ras Effector Interaction Established between Tumour Suppressor NORE1A and Ras Switch II EMBO J. 2008, 27, 1995-2005 10.1038/emboj.2008.125
166. Bunney, T. D.; Harris, R.; Gandarillas, N. L.; Josephs, M. B.; Roe, S. M.; Sorli, S. C.; Paterson, H. F.; Rodrigues-Lima, F.; Esposito, D.; Ponting, C. P. et al. Structural and Mechanistic Insights into Ras Association Domains of Phospholipase C Epsilon Mol. Cell 2006, 21, 495-507 10.1016/j.molcel.2006.01.008
167. Qamra, R.; Hubbard, S. R. Structural Basis for the Interaction of the Adaptor Protein grb14 with Activated Ras PLoS One 2013, 8, e72473 10.1371/journal.pone.0072473
168. Scheffzek, K.; Grünewald, P.; Wohlgemuth, S.; Kabsch, W.; Tu, H.; Wigler, M.; Wittinghofer, A.; Herrmann, C. The Ras-Byr2RBD Complex: Structural Basis for Ras Effector Recognition in Yeast Structure 2001, 9, 1043-1050 10.1016/S0969-2126(01)00674-8
169. Holzapfel, G.; Buhrman, G.; Mattos, C. Shift in the Equilibrium between on and off States of the Allosteric Switch in Ras-GppNHp Affected by Small Molecules and Bulk Solvent Composition Biochemistry 2012, 51, 6114-6126 10.1021/bi300509j
170. Fraser, J. S.; van den Bedem, H.; Samelson, A. J.; Lang, P. T.; Holton, J. M.; Echols, N.; Alber, T. Accessing Protein Conformational Ensembles Using Room-Temperature X-Ray Crystallography Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 16247-16252 10.1073/pnas.1111325108
171. Spiegel, J.; Cromm, P. M.; Itzen, A.; Goody, R. S.; Grossmann, T. N.; Waldmann, H. Direct Targeting of Rab-GTPase-Effector Interactions Angew. Chem.; Int. Ed. 2014, 53, 2498-2503 10.1002/anie.201308568
172. Muegge, I.; Schweins, T.; Langen, R.; Warshel, A. Electrostatic Control of GTP and GDP Binding in the Oncoprotein p21ras Structure 1996, 4, 475-489 10.1016/S0969-2126(96)00052-4
173. Buhrman, G.; O'Connor, C.; Zerbe, B.; Kearney, B. M.; Napoleon, R.; Kovrigina, E. A.; Vajda, S.; Kozakov, D.; Kovrigin, E. L.; Mattos, C. Analysis of Binding Site Hot Spots on the Surface of Ras GTPase J. Mol. Biol. 2011, 413, 773-789 10.1016/j.jmb.2011.09.011
174. Gorfe, A. A.; Grant, B. J.; McCammon, J. A. Mapping the Nucleotide and Isoform-Dependent Structural and Dynamical Features of Ras Proteins Structure 2008, 16, 885-896 10.1016/j.str.2008.03.009
175. Buhrman, G.; Holzapfel, G.; Fetics, S.; Mattos, C. Allosteric Modulation of Ras Positions Q61 for a Direct Role in Catalysis Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 4931-4936 10.1073/pnas.0912226107
176. Parker, J. A.; Mattos, C. The Ras-Membrane Interface: Isoform-Specific Differences in the Catalytic Domain Mol. Cancer Res. 2015, 13, 595-603 10.1158/1541-7786.MCR-14-0535
177. Stouten, P. F.; Sander, C.; Wittinghofer, A.; Valencia, A. How Does the Switch II Region of G-Domains Work? FEBS Lett. 1993, 320, 1-6 10.1016/0014-5793(93)81644-F
178. H Prevent Its Activation by GTP Mol. Cell. Biol. 1991, 11, 4822-4829 10.1128/MCB.11.10.4822
179. Farrar, C. T.; Halkides, C. J.; Singel, D. J. The Frozen Solution Structure of p21 Ras Determined by ESEEM Spectroscopy Reveals Weak Coordination of Thr35 to the Active Site Metal Ion Structure 1997, 5, 1055-1066 10.1016/S0969-2126(97)00257-8
180. 2+ J. Mol. Biol. 1997, 266, 847-856 10.1006/jmbi.1996.0814
181. Rudack, T.; Xia, F.; Schlitter, J.; Kötting, C.; Gerwert, K. The Role of Magnesium for Geometry and Charge in GTP Hydrolysis, Revealed by Quantum Mechanics/Molecular Mechanics Simulations Biophys. J. 2012, 103, 293-302 10.1016/j.bpj.2012.06.015
182. Xia, F.; Rudack, T.; Kötting, C.; Schlitter, J.; Gerwert, K. The Specific Vibrational Modes of GTP in Solution and Bound to Ras: A Detailed Theoretical Analysis by QM/MM Simulations Phys. Chem. Chem. Phys. 2011, 13, 21451-24560 10.1039/c1cp22741f
183. Khrenova, M. G.; Mironov, V. A.; Grigorenko, B. L.; Nemukhin, A. V. Modeling the Role of G12V and G13V Ras Mutations in the Ras-GAP-Catalyzed Hydrolysis Reaction of Guanosine Triphosphate Biochemistry 2014, 53, 7093-7099 10.1021/bi5011333
184. Martín-García, F.; Mendieta-Moreno, J. I.; López-Vinas, E.; Gómez-Puertas, P.; Mendieta, J. The Role of Gln 61 in HRas GTP Hydrolysis: A Quantum Mechanics/Molecular Mechanics Study Biophys. J. 2012, 102, 152-157 10.1016/j.bpj.2011.11.4005
185. Chung, H. H.; Benson, D. R.; Schultz, P. G. Probing the Structure and Mechanism of Ras Protein with an Expanded Genetic Code Science 1993, 259, 806-809 10.1126/science.8430333
186. Shurki, A.; Warshel, A. Why Does the Ras Switch "Break" by Oncogenic Mutations? Proteins: Struct.; Funct.; Genet. 2004, 55, 1-10 10.1002/prot.20004
187. Abankwa, D.; Hanzal-Bayer, M.; Ariotti, N.; Plowman, S. J.; Gorfe, A. A.; Parton, R. G.; McCammon, J. A.; Hancock, J. F. A Novel Switch Region Regulates H-Ras Membrane Orientation and Signal Output EMBO J. 2008, 27, 727-735 10.1038/emboj.2008.10
188. Acharya, K. R.; Lloyd, M. D. The Advantages and Limitations of Protein Crystal Structures Trends Pharmacol. Sci. 2005, 26, 10-14 10.1016/j.tips.2004.10.011
189. Kraulis, P. J.; Domaille, P. J.; Campbell-Burk, S. L.; Van Aken, T.; Laue, E. D. Solution Structure and Dynamics of Ras p21·GDP Determined by Heteronuclear Three- and Four-Dimensional NMR Spectroscopy Biochemistry 1994, 33, 3515-3531 10.1021/bi00178a008
190. Trahey, M.; McCormick, F. A Cytoplasmic Protein Stimulates Normal N-Ras p21 GTPase, but Does Not Affect Oncogenic Mutants Science 1987, 238, 542-545 10.1126/science.2821624
191. Ito, Y.; Yamasaki, K.; Iwahara, J.; Terada, T.; Kamiya, A.; Shirouzu, M.; Muto, Y.; Kawai, G.; Yokoyama, S.; Laue, E. D. et al. Regional Polysterism in the GTP-Bound Form of the Human c-Ha-Ras Protein Biochemistry 1997, 36, 9109-9119 10.1021/bi970296u
192. Araki, M.; Shima, F.; Yoshikawa, Y.; Muraoka, S.; Ijiri, Y.; Nagahara, Y.; Shirono, T.; Kataoka, T.; Tamura, A. Solution Structure of the State 1 Conformer of GTP-Bound H-Ras Protein and Distinct Dynamic Properties between the State 1 and State 2 Conformers J. Biol. Chem. 2011, 286, 39644-39653 10.1074/jbc.M111.227074
193. Boriack-sjodin, P. A.; Margarit, S. M.; Bar-Sagi, D.; Kuriyan, J. The Structural Basis of the Activation of Ras by Sos Nature 1998, 394, 337-343 10.1038/28548
194. Thapar, R.; Williams, J. G.; Campbell, S. L. NMR Characterization of Full-Length Farnesylated and Non-Farnesylated H-Ras and Its Implications for Raf Activation J. Mol. Biol. 2004, 343, 1391-1408 10.1016/j.jmb.2004.08.106
195. Chavan, T. S.; Jang, H.; Khavrutskii, L.; Abraham, S. J.; Banerjee, A.; Freed, B. C.; Johannessen, L.; Tarasov, S. G.; Gaponenko, V.; Nussinov, R. et al. High Affinity Interaction of K-Ras4B Hypervariable Region with Ras Active Site Biophys. J. 2015, 109, 2602-2613 10.1016/j.bpj.2015.09.034
196. Akashi, S.; Shirouzu, M.; Terada, T.; Ito, Y.; Yokoyama, S.; Takio, K. Characterization of the Structural Difference between Active and Inactive Forms of the Ras Protein by Chemical Modification Followed by Mass Spectrometric Peptide Mapping Anal. Biochem. 1997, 248, 15-25 10.1006/abio.1997.2122
197. Lu, S.; Banerjee, A.; Jang, H.; Zhang, J.; Gaponenko, V.; Nussinov, R. GTP Binding and Oncogenic Mutations May Attenuate Hypervariable Region (HVR)-Catalytic Domain Interactions in Small GTPase K-Ras4B, Exposing the Effector Binding Site J. Biol. Chem. 2015, 290, 28887-28900 10.1074/jbc.M115.664755
198. Abraham, S. J.; Nolet, R. P.; Calvert, R. J.; Anderson, L. M.; Gaponenko, V. The Hypervariable Region of K-Ras4B Is Responsible for Its Specific Interactions with Calmodulin Biochemistry 2009, 48, 7575-7583 10.1021/bi900769j
199. Shen, Q.; Wang, G.; Li, S.; Liu, X.; Lu, S.; Chen, Z.; Song, K.; Yan, J.; Geng, L.; Huang, Z.; Huang, W.; Chen, G.; Zhang, J. ASD v3.0: unraveling allosteric regulation with structural mechanisms and biological networks Nucleic Acids Res. 2016, 44, D527-D535 10.1093/nar/gkv902
200. Tsai, C.-J.; Nussinov, R. A Unified View of "How Allostery Works PLoS Comput. Biol. 2014, 10, e1003394 10.1371/journal.pcbi.1003394
201. Nussinov, R.; Tsai, C.-J. Allostery in Disease and in Drug Discovery Cell 2013, 153, 293-305 10.1016/j.cell.2013.03.034
202. Lu, S.; Li, S.; Zhang, J. Harnessing Allostery: A Novel Approach to Drug Discovery Med. Res. Rev. 2014, 34, 1242-1285 10.1002/med.21317
203. Lu, S.; Huang, W.; Zhang, J. Recent Computational Advances in the Identification of Allosteric Sites in Proteins Drug Discovery Today 2014, 19, 1595-1600 10.1016/j.drudis.2014.07.012
204. Prakash, P.; Gorfe, A. A. Lessons from Computer Simulations of Ras Proteins in Solution and in Membrane Biochim. Biophys. Acta, Gen. Subj. 2013, 1830, 5211-5218 10.1016/j.bbagen.2013.07.024
205. Grant, B. J.; Gorfe, A. A.; McCammon, J. A. Ras Conformational Switching: Simulating Nucleotide-Dependent Conformational Transitions with Accelerated Molecular Dynamics PLoS Comput. Biol. 2009, 5, e1000325 10.1371/journal.pcbi.1000325
206. Kapoor, A.; Travesset, A. Differential Dynamics of RAS Isoforms in GDP- and GTP-Bound States Proteins: Struct.; Funct.; Genet. 2015, 83, 1091-1106 10.1002/prot.24805
207. Raimondi, F.; Portella, G.; Orozco, M.; Fanelli, F. Nucleotide Binding Switches the Information Flow in Ras GTPases PLoS Comput. Biol. 2011, 7, e1001098 10.1371/journal.pcbi.1001098
208. Ma, J.; Karplus, M. Ligand-Induced Conformational Changes in Ras p21: A Normal Mode and Energy Minimization Analysis J. Mol. Biol. 1997, 274, 114-131 10.1006/jmbi.1997.1313
209. ras-GTP: The Catalytic Conformation of the Molecular Switch II Proteins: Struct.; Funct.; Genet. 2001, 45, 297-312 10.1002/prot.1150
210. O'Connor, C.; Kovrigin, E. L. Global Conformational Dynamics in Ras Biochemistry 2008, 47, 10244-10246 10.1021/bi801076c
211. Diaz, J. F.; Wroblowski, B.; Schlitter, J.; Engelborghs, Y. Calculation of Pathways for the Conformational Transition between the GTP- and GDP-Bound States of the Ha-Ras-p21 Protein: Calculations with Explicit Solvent Simulations and Comparison with Calculations in Vacuum Proteins: Struct.; Funct.; Genet. 1997, 28, 434-451 10.1002/(SICI)1097-0134(199707)28:3<434::AID-PROT12>3.3.CO;2-T
212. ras in Complex with GTP: New Insights into the Role of Water Molecules in the GTP Hydrolysis Reaction of Ras-like Proteins Structure 1999, 7, 1311-1124 10.1016/S0969-2126(00)80021-0
213. Kobayashi, C.; Saito, S. Relation between the Conformational Heterogeneity and Reaction Cycle of Ras: Molecular Simulation of Ras Biophys. J. 2010, 99, 3726-3734 10.1016/j.bpj.2010.09.063
214. Sharma, N.; Sonavane, U.; Joshi, R. Probing the Wild-Type HRas Activation Mechanism Using Steered Molecular Dynamics, Understanding the Energy Barrier and Role of Water in the Activation Eur. Biophys. J. 2014, 43, 81-95 10.1007/s00249-014-0942-4
215. Kapoor, A.; Travesset, A. Mechanism of the Exchange Reaction in HRAS from Multiscale Modeling PLoS One 2014, 9, e108846 10.1371/journal.pone.0108846
216. Ma, J.; Karplus, M. Molecular Switch in Signal Transduction: Reaction Paths of the Conformational Changes in Ras p21 Proc. Natl. Acad. Sci. U. S. A. 1997, 94, 11905-11910 10.1073/pnas.94.22.11905
217. Lu, S.; Huang, W.; Wang, Q.; Shen, Q.; Li, S.; Nussinov, R.; Zhang, J. The Structural Basis of ATP as an Allosteric Modulator PLoS Comput. Biol. 2014, 10, e1003831 10.1371/journal.pcbi.1003831
218. Yamasaki, K.; Shirouzu, M.; Muto, Y.; Fujita-Yoshigaki, J.; Koide, H.; Ito, Y.; Kawai, G.; Hattori, S.; Yokoyama, S.; Nishimura, S.; Miyazawa, T. Site-Directed Mutagenesis, Fluorescence, and Two-Dimensional NMR Studies on Microenvironments of Effector Region Aromatic Residues of Human c-Ha-Ras Protein Biochemistry 1994, 33, 65-73 10.1021/bi00167a009
219. Lukman, S.; Grant, B. J.; Gorfe, A. A.; Grant, G. H.; McCammon, J. A. The Distinct Conformational Dynamics of K-Ras and H-Ras A59G PLoS Comput. Biol. 2010, 6, e1000922 10.1371/journal.pcbi.1000922
220. Jurnak, F.; Heffron, S.; Bergmann, E. Conformational Changes Involved in the Activation of Ras P21: Implications for Related Proteins Cell 1990, 60, 525-528 10.1016/0092-8674(90)90652-U
221. Ford, B.; Hornak, V.; Kleinman, H.; Nassar, N. Structure of a Transient Intermediate for GTP Hydrolysis by Ras Structure 2006, 14, 427-436 10.1016/j.str.2005.12.010
222. Liao, J.; Shima, F.; Araki, M.; Ye, M.; Muraoka, S.; Sugimoto, T.; Kawamura, M.; Yamamoto, N.; Tamura, A.; Kataoka, T. Two Conformational States of Ras GTPase Exhibit Differential GTP-Binding Kinetics Biochem. Biophys. Res. Commun. 2008, 369, 327-332 10.1016/j.bbrc.2008.01.169
223. ras and in Its Complexes with the Effector Protein Raf-RBD and the GTPase Activating Protein GAP Biochemistry 1996, 35, 10308-10320 10.1021/bi952858k
224. Muraoka, S.; Shima, F.; Araki, M.; Inoue, T.; Yoshimoto, A.; Ijiri, Y.; Seki, N.; Tamura, A.; Kumasaka, T.; Yamamoto, M. et al. Crystal Structures of the State 1 Conformations of the GTP-Bound H-Ras Protein and Its Oncogenic G12V and Q61L Mutants FEBS Lett. 2012, 586, 1715-1718 10.1016/j.febslet.2012.04.058
225. Shima, F.; Matsumoto, S.; Yoshikawa, Y.; Kawamura, T.; Isa, M.; Kataoka, T. Current Status of the Development of Ras Inhibitors J. Biochem. 2015, 158, 91-99 10.1093/jb/mvv060
226. Tanaka, T.; Rabbitts, T. H. Functional Intracellular Antibody Fragments Do Not Require Invariant Intra-Domain Disulfide Bonds J. Mol. Biol. 2008, 376, 749-757 10.1016/j.jmb.2007.11.085
227. Tanaka, T.; Williams, R. L.; Rabbitts, T. H. Tumour Prevention by a Single Antibody Domain Targeting the Interaction of Signal Transduction Proteins with RAS EMBO J. 2007, 26, 3250-3259 10.1038/sj.emboj.7601744
228. Linnemann, T.; Kiel, C.; Herter, P.; Herrmann, C. The Activation of RalGDS Can Be Achieved Independently of Its Ras Binding Domain. Implications of an Activation Mechanism in Ras Effector Specificity and Signal Distribution J. Biol. Chem. 2002, 277, 7831-7837 10.1074/jbc.M110800200
229. Kalbitzer, H. R.; Spoerner, M.; Ganser, P.; Hozsa, C.; Kremer, W. Fundamental Link between Folding States and Functional States of Proteins J. Am. Chem. Soc. 2009, 131, 16714-16719 10.1021/ja904314q
230. Spoerner, M.; Nuehs, A.; Ganser, P.; Herrmann, C.; Wittinghofer, A.; Kalbitzer, H. R. Conformational States of Ras Complexed with the GTP Analogue GppNHp or GppCH2p: Implications for the Interaction with Effector Proteins Biochemistry 2005, 44, 2225-2236 10.1021/bi0488000
231. Spoerner, M.; Nuehs, A.; Herrmann, C.; Steiner, G.; Kalbitzer, H. R. Slow Conformational Dynamics of the Guanine Nucleotide-Binding Protein Ras Complexed with the GTP Analogue GTPgammaS FEBS J. 2007, 274, 1419-1433 10.1111/j.1742-4658.2007.05681.x
232. Spoerner, M.; Hozsa, C.; Poetzl, J. A.; Reiss, K.; Ganser, P.; Geyer, M.; Kalbitzer, H. R. Conformational States of Human Rat Sarcoma (Ras) Protein Complexed with Its Natural Ligand GTP and Their Role for Effector Interaction and GTP Hydrolysis J. Biol. Chem. 2010, 285, 39768-39778 10.1074/jbc.M110.145235
233. Spoerner, M.; Herrmann, C.; Vetter, I. R.; Kalbitzer, H. R.; Wittinghofer, A. Dynamic Properties of the Ras Switch I Region and Its Importance for Binding to Effectors Proc. Natl. Acad. Sci. U. S. A. 2001, 98, 4944-4949 10.1073/pnas.081441398
234. Shinoda, S. Dynamic Cyclen-Metal Complexes for Molecular Sensing and Chirality Signaling Chem. Soc. Rev. 2013, 42, 1825-1835 10.1039/C2CS35295H
235. Rosnizeck, I. C.; Graf, T.; Spoerner, M.; Tränkle, J.; Filchtinski, D.; Herrmann, C.; Gremer, L.; Vetter, I. R.; Wittinghofer, A.; König, B. et al. Stabilizing a Weak Binding State for Effectors in the Human Ras Protein by Cyclen Complexes Angew. Chem.; Int. Ed. 2010, 49, 3830-3833 10.1002/anie.200907002
236. 2+-Cyclen as Probe to Identify Conformational States in Guanine Nucleotide Binding Proteins J. Am. Chem. Soc. 2011, 133, 2048-2051 10.1021/ja108779j
237. Rosnizeck, I. C.; Filchtinski, D.; Lopes, R. P.; Kieninger, B.; Herrmann, C.; Kalbitzer, H. R.; Spoerner, M. Elucidating the Mode of Action of a Typical Ras State 1(T) Inhibitor Biochemistry 2014, 53, 3867-3878 10.1021/bi401689w
238. Rosnizeck, I. C.; Spoerner, M.; Harsch, T.; Kreitner, S.; Filchtinski, D.; Herrmann, C.; Engel, D.; König, B.; Kalbitzer, H. R. Metal-bis(2-Picolyl)amine Complexes as State 1(T) Inhibitors of Activated Ras Protein Angew. Chem.; Int. Ed. 2012, 51, 10647-10651 10.1002/anie.201204148
239. Erlanson, D. A.; Wells, J. A.; Braisted, A. C. Tethering: Fragment-Based Drug Discovery Annu. Rev. Biophys. Biomol. Struct. 2004, 33, 199-223 10.1146/annurev.biophys.33.110502.140409
240. Nussinov, R.; Tsai, C.-J. The Design of Covalent Allosteric Drugs Annu. Rev. Pharmacol. Toxicol. 2015, 55, 249-267 10.1146/annurev-pharmtox-010814-124401
241. Mattos, C. Ras: Structural Details to Guide Direct Targeting Aging 2015, 7, 344-345
242. Mosteller, R. D.; Han, J.; Broek, D. Identification of Residues of the H-Ras Protein Critical for Functional Interaction with Guanine Nucleotide Exchange Factors Mol. Cell. Biol. 1994, 14, 1104-1112 10.1128/MCB.14.2.1104
243. Cherfils, J.; Chardin, P. GEFs: Structural Basis for Their Activation of Small GTP-Binding Proteins Trends Biochem. Sci. 1999, 24, 306-311 10.1016/S0968-0004(99)01429-2
244. Mitin, N.; Rossman, K. L.; Der, C. J. Signaling Interplay in Ras Superfamily Function Curr. Biol. 2005, 15, R563-R574 10.1016/j.cub.2005.07.010
245. Campbell, S. L.; Khosravi-Far, R.; Rossman, K. L.; Clark, G. J.; Der, C. J. Increasing Complexity of Ras Signaling Oncogene 1998, 17, 1395-1413 10.1038/sj.onc.1202174
246. Chardin, P.; Camonis, J. H.; Gale, N. W.; van Aelst, L.; Schlessinger, J.; Wigler, M. H.; Bar-Sagi, D. Human Sos1: A Guanine Nucleotide Exchange Factor for Ras That Binds to GRB2 Science 1993, 260, 1338-1343 10.1126/science.8493579
247. Quilliam, L. A.; Hisaka, M. M.; Zhong, S.; Lowry, A.; Mosteller, R. D.; Han, J.; Drugan, J. K.; Broek, D.; Campbell, S. L.; Der, C. J. Involvement of the Switch 2 Domain of Ras in Its Interaction with Guanine Nucleotide Exchange Factors J. Biol. Chem. 1996, 271, 11076-11082 10.1074/jbc.271.19.11076
248. Bos, J. L.; Rehmann, H.; Wittinghofer, A. Review GEFs and GAPs: Critical Elements in the Control of Small G Proteins Cell 2007, 129, 865-877 10.1016/j.cell.2007.05.018
249. Margarit, S. M.; Sondermann, H.; Hall, B. E.; Nagar, B.; Hoelz, A.; Pirruccello, M.; Bar-Sagi, D.; Kuriyan, J. Structural Evidence for Feedback Activation by Ras·GTP of the Ras-Specific Nucleotide Exchange Factor SOS Cell 2003, 112, 685-695 10.1016/S0092-8674(03)00149-1
250. Hall, B. E.; Yang, S. S.; Boriack-Sjodin, P. A.; Kuriyan, J.; Bar-Sagi, D. Structure-Based Mutagenesis Reveals Distinct Functions for Ras Switch 1 and Switch 2 in Sos-Catalyzed Guanine Nucleotide Exchange J. Biol. Chem. 2001, 276, 27629-27637 10.1074/jbc.M101727200
251. Boykevisch, S.; Zhao, C.; Sondermann, H.; Philippidou, P.; Halegoua, S.; Kuriyan, J.; Bar-Sagi, D. Regulation of Ras Signaling Dynamics by Sos-Mediated Positive Feedback Curr. Biol. 2006, 16, 2173-2179 10.1016/j.cub.2006.09.033
252. Vo, U.; Vajpai, N.; Flavell, L.; Bobby, R.; Breeze, A. L.; Embrey, K. J.; Golovanov, A. P. Monitoring Ras Interactions with the Nucleotide Exchange Factor Sos Using Site-Specific NMR Reporter Signals and Intrinsic Fluorescence J. Biol. Chem. 2015, 10.1074/jbc.M115.691238
253. Das, J.; Ho, M.; Zikherman, J.; Govern, C.; Yang, M.; Weiss, A.; Chakraborty, A. K.; Roose, J. P. Digital Signaling and Hysteresis Characterize Ras Activation in Lymphoid Cells Cell 2009, 136, 337-351 10.1016/j.cell.2008.11.051
254. Iversen, L.; Tu, H.-L.; Lin, W.-C.; Christensen, S. M.; Abel, S. M.; Iwig, J.; Wu, H.-J.; Gureasko, J.; Rhodes, C.; Petit, R. S. et al. Molecular Kinetics. Ras Activation by SOS: Allosteric Regulation by Altered Fluctuation Dynamics Science 2014, 345, 50-54 10.1126/science.1250373
255. Sondermann, H.; Soisson, S. M.; Boykevisch, S.; Yang, S.; Bar-Sagi, D.; Kuriyan, J. Structural Analysis of Autoinhibition in the Ras Activator Son of Sevenless Cell 2004, 119, 393-405 10.1016/j.cell.2004.10.005
256. Yadav, K. K.; Bar-Sagi, D. Allosteric Gating of Son of Sevenless Activity by the Histone Domain Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 3436-3440 10.1073/pnas.0914315107
257. Corbalan-Garcia, S.; Margarit, S. M.; Galron, D.; Yang, S. S.; Bar-Sagi, D. Regulation of Sos Activity by Intramolecular Interactions Mol. Cell. Biol. 1998, 18, 880-886 10.1128/MCB.18.2.880
258. Gureasko, J.; Galush, W. J.; Boykevisch, S.; Sondermann, H.; Bar-Sagi, D.; Groves, J. T.; Kuriyan, J. Membrane-Dependent Signal Integration by the Ras Activator Son of Sevenless Nat. Struct. Mol. Biol. 2008, 15, 452-461 10.1038/nsmb.1418
259. Roose, J. P.; Mollenauer, M.; Ho, M.; Kurosaki, T.; Weiss, A. Unusual Interplay of Two Types of Ras Activators, RasGRP and SOS, Establishes Sensitive and Robust Ras Activation in Lymphocytes Mol. Cell. Biol. 2007, 27, 2732-2745 10.1128/MCB.01882-06
260. Burns, M. C.; Sun, Q.; Daniels, R. N.; Camper, D.; Kennedy, J. P.; Phan, J.; Olejniczak, E. T.; Lee, T.; Waterson, A. G.; Rossanese, O. W. et al. Approach for Targeting Ras with Small Molecules That Activate SOS-Mediated Nucleotide Exchange Proc. Natl. Acad. Sci. U. S. A. 2014, 111, 3401-3406 10.1073/pnas.1315798111
261. Sun, Q.; Burke, J. P.; Phan, J.; Burns, M. C.; Olejniczak, E. T.; Waterson, A. G.; Lee, T.; Rossanese, O. W.; Fesik, S. W. Discovery of Small Molecules That Bind to K-Ras and Inhibit Sos-Mediated Activation Angew. Chem.; Int. Ed. 2012, 51, 6140-6143 10.1002/anie.201201358
262. Maurer, T.; Garrenton, L. S.; Oh, A.; Pitts, K.; Anderson, D. J.; Skelton, N. J.; Fauber, B. P.; Pan, B.; Malek, S.; Stokoe, D. et al. Small-Molecule Ligands Bind to a Distinct Pocket in Ras and Inhibit SOS-Mediated Nucleotide Exchange Activity Proc. Natl. Acad. Sci. U. S. A. 2012, 109, 5299-5304 10.1073/pnas.1116510109
263. Schöpel, M.; Jockers, K. F. G.; Düppe, P. M.; Autzen, J.; Potheraveedu, V. N.; Ince, S.; Yip, K. T.; Heumann, R.; Herrmann, C.; Scherkenbeck, J. et al. Bisphenol A Binds to Ras Proteins and Competes with Guanine Nucleotide Exchange: Implications for GTPase-Selective Antagonists J. Med. Chem. 2013, 56, 9664-9672 10.1021/jm401291q
264. Evelyn, C. R.; Duan, X.; Biesiada, J.; Seibel, W. L.; Meller, J.; Zheng, Y. Rational Design of Small Molecule Inhibitors Targeting the Ras GEF, SOS1 Chem. Biol. 2014, 21, 1618-1628 10.1016/j.chembiol.2014.09.018
265. Evelyn, C. R.; Biesiada, J.; Duan, X.; Tang, H.; Shang, X.; Papoian, R.; Seibel, W. L.; Nelson, S.; Meller, J.; Zheng, Y. Combined Rational Design and a High Throughput Screening Platform for Identifying Chemical Inhibitors of a Ras-Activating Enzyme J. Biol. Chem. 2015, 290, 12879-12898 10.1074/jbc.M114.634493
266. Winter, J. J. G.; Anderson, M.; Blades, K.; Brassington, C.; Breeze, A. L.; Chresta, C.; Embrey, K.; Fairley, G.; Faulder, P.; Finlay, M. R. V et al. Small Molecule Binding Sites on the Ras:SOS Complex Can Be Exploited for Inhibition of Ras Activation J. Med. Chem. 2015, 58, 2265-2274 10.1021/jm501660t
267. Hocker, H. J.; Cho, K.-J.; Chen, C.-Y. K.; Rambahal, N.; Sagineedu, S. R.; Shaari, K.; Stanslas, J.; Hancock, J. F.; Gorfe, A. A. Andrographolide Derivatives Inhibit Guanine Nucleotide Exchange and Abrogate Oncogenic Ras Function Proc. Natl. Acad. Sci. U. S. A. 2013, 110, 10201-10206 10.1073/pnas.1300016110
268. Peri, F.; Airoldi, C.; Colombo, S.; Martegani, E.; van Neuren, A. S.; Stein, M.; Marinzi, C.; Nicotra, F. Design, Synthesis and Biological Evaluation of Sugar-Derived Ras Inhibitors ChemBioChem 2005, 6, 1839-1848 10.1002/cbic.200400420
269. Leshchiner, E. S.; Parkhitko, A.; Bird, G. H.; Luccarelli, J.; Bellairs, J. A.; Escudero, S.; Opoku-Nsiah, K.; Godes, M.; Perrimon, N.; Walensky, L. D. Direct Inhibition of Oncogenic KRAS by Hydrocarbon-Stapled SOS1 Helices Proc. Natl. Acad. Sci. U. S. A. 2015, 112, 1761-1766 10.1073/pnas.1413185112
270. Patgiri, A.; Yadav, K. K.; Arora, P. S.; Bar-Sagi, D. An Orthosteric Inhibitor of the Ras-Sos Interaction Nat. Chem. Biol. 2011, 7, 585-587 10.1038/nchembio.612
271. ras and Other GTP-Binding Proteins Nat. Struct. Biol. 1995, 2, 36-44 10.1038/nsb0195-36
272. Scheffzek, K.; Ahmadian, M. R.; Kabsch, W.; Wiesmüller, L.; Lautwein, A.; Schmitz, F.; Wittinghofer, A. The Ras-RasGAP Complex: Structural Basis for GTPase Activation and Its Loss in Oncogenic Ras Mutants Science 1997, 277, 333-338 10.1126/science.277.5324.333
273. Miao, W.; Eichelberger, L.; Baker, L.; Marshall, M. S. p120 Ras GTPase-Activating Protein Interacts with Ras-GTP through Specific Conserved Residues J. Biol. Chem. 1996, 271, 15322-15329 10.1074/jbc.271.26.15322
274. Chung, H. H.; Benson, D. R.; Cornish, V. W.; Schultz, P. G. Probing the Role of Loop 2 in Ras Function with Unnatural Amino Acids Proc. Natl. Acad. Sci. U. S. A. 1993, 90, 10145-10149 10.1073/pnas.90.21.10145
275. ras upon GAP-334 Complexation as Probed by ESEEM Spectroscopy and Molecular-Dynamics Simulation Structure 2000, 8, 1279-1287 10.1016/S0969-2126(00)00532-3
276. Rudack, T.; Xia, F.; Schlitter, J.; Kotting, C.; Gerwert, K. Ras and GTPase-Activating Protein (GAP) Drive GTP into a Precatalytic State as Revealed by Combining FTIR and Biomolecular Simulations Proc. Natl. Acad. Sci. U. S. A. 2012, 109, 15295-15300 10.1073/pnas.1204333109
277. Kötting, C.; Kallenbach, A.; Suveyzdis, Y.; Wittinghofer, A.; Gerwert, K. The GAP Arginine Finger Movement into the Catalytic Site of Ras Increases the Activation Entropy Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 6260-6265 10.1073/pnas.0712095105
278. Ahmadian, M. R.; Stege, P.; Scheffzek, K.; Wittinghofer, A. Confirmation of the Arginine-Finger Hypothesis for the GAP-Stimulated GTP-Hydrolysis Reaction of Ras Nat. Struct. Biol. 1997, 4, 686-689 10.1038/nsb0997-686
279. Bourne, H. R. G Proteins: The Arginine Finger Strikes Again Nature 1997, 389, 673-674 10.1038/39470
280. Scheffzek, K.; Ahmadian, M. R.; Wittinghofer, A. GTPase-Activating Proteins: Helping Hands to Complement an Active Site Trends Biochem. Sci. 1998, 23, 257-262 10.1016/S0968-0004(98)01224-9
281. Glennon, T. M.; Villà, J.; Warshel, A. How Does GAP Catalyze the GTPase Reaction of Ras? A Computer Simulation Study Biochemistry 2000, 39, 9641-9651 10.1021/bi000640e
282. Grigorenko, B. L.; Nemukhin, A. V.; Topol, I. A.; Cachau, R. E.; Burt, S. K. QM/MM Modeling the Ras-GAP Catalyzed Hydrolysis of Guanosine Triphosphate Proteins: Struct.; Funct.; Genet. 2005, 60, 495-503 10.1002/prot.20472
283. Futatsugi, N.; Hata, M.; Hoshino, T.; Tsuda, M. Ab Initio Study of the Role of Lysine 16 for the Molecular Switching Mechanism of Ras Protein p21 Biophys. J. 1999, 77, 3287-3292 10.1016/S0006-3495(99)77159-6
284. Kötting, C.; Blessenohl, M.; Suveyzdis, Y.; Goody, R. S.; Wittinghofer, A.; Gerwert, K. A Phosphoryl Transfer Intermediate in the GTPase Reaction of Ras in Complex with Its GTPase-Activating Protein Proc. Natl. Acad. Sci. U. S. A. 2006, 103, 13911-13916 10.1073/pnas.0604128103
285. Gideon, P.; John, J.; Frech, M.; Lautwein, A.; Clark, R.; Scheffler, J. E.; Wittinghofer, A. Mutational and Kinetic Analyses of the GTPase-Activating Protein (GAP)-p21 Interaction: The C-Terminal Domain of GAP Is Not Sufficient for Full Activity Mol. Cell. Biol. 1992, 12, 2050-2056 10.1128/MCB.12.5.2050
286. Langen, R.; Schweins, T.; Warshel, A. On the Mechanism of Guanosine Triphosphate Hydrolysis in Ras p21 Proteins Biochemistry 1992, 31, 8691-8696 10.1021/bi00152a002
287. Stafford, A. J.; Walker, D. M.; Webb, L. J. Electrostatic Effects of Mutations of Ras Glutamine 61 Measured Using Vibrational Spectroscopy of a Thiocyanate Probe Biochemistry 2012, 51, 2757-2767 10.1021/bi201225p
288. ras Effector Binding Domain Science 1988, 240, 518-521 10.1126/science.2833817
289. Resat, H.; Straatsma, T. P.; Dixon, D. A.; Miller, J. H. The Arginine Finger of RasGAP Helps Gln-61 Align the Nucleophilic Water in GAP-Stimulated Hydrolysis of GTP Proc. Natl. Acad. Sci. U. S. A. 2001, 98, 6033-6038 10.1073/pnas.091506998
290. Maegley, K. A.; Admiraal, S. J.; Herschlag, D. Ras-Catalyzed Hydrolysis of GTP: A New Perspective from Model Studies Proc. Natl. Acad. Sci. U. S. A. 1996, 93, 8160-8166 10.1073/pnas.93.16.8160
291. Wittinghofer, A.; Herrmann, C. Ras-Effector Interactions, the Problem of Specificity FEBS Lett. 1995, 369, 52-56 10.1016/0014-5793(95)00667-X
292. Marshall, C. J. Ras Effectors Curr. Opin. Cell Biol. 1996, 8, 197-204 10.1016/S0955-0674(96)80066-4
293. McCormick, F.; Wittinghofer, A. Interactions between Ras Proteins and Their Effectors Curr. Opin. Biotechnol. 1996, 7, 449-456 10.1016/S0958-1669(96)80123-6
294. Koide, H.; Satoh, T.; Nakafuku, M.; Kaziro, Y. GTP-Dependent Association of Raf-1 with Ha-Ras: Identification of Raf as a Target Downstream of Ras in Mammalian Cells Proc. Natl. Acad. Sci. U. S. A. 1993, 90, 8683-8686 10.1073/pnas.90.18.8683
295. ras and the Ras-Binding Domain of the Human Raf-1 Protein Kinase J. Biol. Chem. 1995, 270, 2901-2905 10.1074/jbc.270.7.2901
296. Mott, H. R.; Owen, D. Structures of Ras Superfamily Effector Complexes: What Have We Learnt in Two Decades? Crit. Rev. Biochem. Mol. Biol. 2015, 50, 85-133 10.3109/10409238.2014.999191
297. Kolch, W. Meaningful Relationships: The Regulation of the Ras/Raf/MEK/ERK Pathway by Protein Interactions Biochem. J. 2000, 351, 289-305 10.1042/bj3510289
298. Roskoski, R. RAF Protein-Serine/Threonine Kinases: Structure and Regulation Biochem. Biophys. Res. Commun. 2010, 399, 313-317 10.1016/j.bbrc.2010.07.092
299. Vojtek, A. B.; Hollenberg, S. M.; Cooper, J. A. Mammalian Ras Interacts Directly with the Serine/threonine Kinase Raf Cell 1993, 74, 205-214 10.1016/0092-8674(93)90307-C
300. Chuang, E.; Barnard, D.; Hettich, L.; Zhang, X. F.; Avruch, J.; Marshall, M. S. Critical Binding and Regulatory Interactions between Ras and Raf Occur through a Small, Stable N-Terminal Domain of Raf and Specific Ras Effector Residues Mol. Cell. Biol. 1994, 14, 5318-5325 10.1128/MCB.14.8.5318
301. Ghosh, S.; Bell, R. M. Identification of Discrete Segments of Human Raf-1 Kinase Critical for High Affinity Binding to Ha-Ras J. Biol. Chem. 1994, 269, 30785-30788
302. Gohlke, H.; Kiel, C.; Case, D. A. Insights into Protein-Protein Binding by Binding Free Energy Calculation and Free Energy Decomposition for the Ras-Raf and Ras-RalGDS Complexes J. Mol. Biol. 2003, 330, 891-913 10.1016/S0022-2836(03)00610-7
303. ras Proteins Bind to the Amino-Terminal Regulatory Domain of c-Raf-1 Nature 1993, 364, 308-313 10.1038/364308a0
304. Drugan, J. K.; Khosravi-Far, R.; White, M. A.; Der, C. J.; Sung, Y. J.; Hwang, Y. W.; Campbell, S. L. Ras Interaction with Two Distinct Binding Domains in Raf-1 May Be Required for Ras Transformation J. Biol. Chem. 1996, 271, 233-237 10.1074/jbc.271.1.233
305. Akasaka, K.; Tamada, M.; Wang, F.; Kariya, K.; Shima, F.; Kikuchi, A.; Yamamoto, M.; Shirouzu, M.; Yokoyama, S.; Kataoka, T. Differential Structural Requirements for Interaction of Ras Protein with Its Distinct Downstream Effectors J. Biol. Chem. 1996, 271, 5353-5360 10.1074/jbc.271.10.5353
306. Winkler, D. G.; Johnson, J. C.; Cooper, J. A.; Vojtek, A. B. Identification and Characterization of Mutations in Ha-Ras That Selectively Decrease Binding to cRaf-1 J. Biol. Chem. 1997, 272, 24402-24409 10.1074/jbc.272.39.24402
307. Hu, C. D.; Kariya, K.; Tamada, M.; Akasaka, K.; Shirouzu, M.; Yokoyama, S.; Kataoka, T. Cysteine-Rich Region of Raf-1 Interacts with Activator Domain of Post-Translationally Modified Ha-Ras J. Biol. Chem. 1995, 270, 30274-30277 10.1074/jbc.270.51.30274
308. Williams, J. G.; Drugan, J. K.; Yi, G. S.; Clark, G. J.; Der, C. J.; Campbell, S. L. Elucidation of Binding Determinants and Functional Consequences of Ras/Raf-Cysteine-Rich Domain Interactions J. Biol. Chem. 2000, 275, 22172-22179 10.1074/jbc.M000397200
309. Bondeva, T.; Balla, A.; Várnai, P.; Balla, T. Structural Determinants of Ras-Raf Interaction Analyzed in Live Cells Mol. Biol. Cell 2002, 13, 2323-2333 10.1091/mbc.E02-01-0019
310. Nassar, N.; Horn, G.; Herrmann, C.; Block, C.; Janknecht, R.; Wittinghofer, A. Ras/Rap Effector Specificity Determined by Charge Reversal Nat. Struct. Biol. 1996, 3, 723-729 10.1038/nsb0896-723
311. Nassar, N.; Horn, G.; Herrmann, C.; Scherer, A.; McCormick, F.; Wittinghofer, A. The 2.2 Å Crystal Structure of the Ras-Binding Domain of the Serine/Threonine Kinase c-Raf1 in Complex with Rap1A and a GTP Analogue Nature 1995, 375, 554-560 10.1038/375554a0
312. Terada, T.; Ito, Y.; Shirouzu, M.; Tateno, M.; Hashimoto, K.; Kigawa, T.; Ebisuzaki, T.; Takio, K.; Shibata, T.; Yokoyama, S. et al. Nuclear Magnetic Resonance and Molecular Dynamics Studies on the Interactions of the Ras-Binding Domain of Raf-1 with Wild-Type and Mutant Ras Proteins J. Mol. Biol. 1999, 286, 219-232 10.1006/jmbi.1998.2472
313. Block, C.; Janknecht, R.; Herrmann, C.; Nassar, N.; Wittinghofer, A. Quantitative Structure-Activity Analysis Correlating Ras/Raf Interaction in Vitro to Raf Activation in Vivo Nat. Struct. Biol. 1996, 3, 244-251 10.1038/nsb0396-244
314. Filchtinski, D.; Sharabi, O.; Rüppel, A.; Vetter, I. R.; Herrmann, C.; Shifman, J. M. What Makes Ras an Efficient Molecular Switch: A Computational, Biophysical, and Structural Study of Ras-GDP Interactions with Mutants of Raf J. Mol. Biol. 2010, 399, 422-435 10.1016/j.jmb.2010.03.046
315. Engelman, J. A.; Luo, J.; Cantley, L. C. The Evolution of Phosphatidylinositol 3-Kinases as Regulators of Growth and Metabolism Nat. Rev. Genet. 2006, 7, 606-619 10.1038/nrg1879
316. Cantley, L. C. The Phosphoinositide 3-Kinase Pathway Science 2002, 296, 1655-1657 10.1126/science.296.5573.1655
317. Liu, P.; Cheng, H.; Roberts, T. M.; Zhao, J. J. Targeting the Phosphoinositide 3-Kinase Pathway in Cancer Nat. Rev. Drug Discovery 2009, 8, 627-644 10.1038/nrd2926
318. Castellano, E.; Downward, J. Downward, J. RAS Interaction with PI3K: More Than Just Another Effector Pathway Genes Cancer 2011, 2, 261-274 10.1177/1947601911408079
319. Zhao, Y.; Zhang, X.; Chen, Y.; Lu, S.; Peng, Y.; Wang, X.; Guo, C.; Zhou, A.; Zhang, J.; Luo, Y. et al. Crystal Structures of PI3Kα Complexed with PI103 and Its Derivatives: New Directions for Inhibitors Design ACS Med. Chem. Lett. 2014, 5, 138-142 10.1021/ml400378e
320. Huang, C.-H.; Mandelker, D.; Schmidt-Kittler, O.; Samuels, Y.; Velculescu, V. E.; Kinzler, K. W.; Vogelstein, B.; Gabelli, S. B.; Amzel, L. M. The Structure of a Human p110α/p85α Complex Elucidates the Effects of Oncogenic PI3Kα Mutations Science 2007, 318, 1744-1748 10.1126/science.1150799
321. Fritsch, R.; de Krijger, I.; Fritsch, K.; George, R.; Reason, B.; Kumar, M. S.; Diefenbacher, M.; Stamp, G.; Downward, J. RAS and RHO Families of GTPases Directly Regulate Distinct Phosphoinositide 3-Kinase Isoforms Cell 2013, 153, 1050-1063 10.1016/j.cell.2013.04.031
322. Rubio, I.; Rodriguez-Viciana, P.; Downward, J.; Wetzker, R. Interaction of Ras with Phosphoinositide 3-Kinase Gamma Biochem. J. 1997, 326, 891-895 10.1042/bj3260891
323. Vanhaesebroeck, B.; Welham, M. J.; Kotani, K.; Stein, R.; Warne, P. H.; Zvelebil, M. J.; Higashi, K.; Volinia, S.; Downward, J.; Waterfield, M. D. P110, a Novel Phosphoinositide 3-Kinase in Leukocytes Proc. Natl. Acad. Sci. U. S. A. 1997, 94, 4330-4335 10.1073/pnas.94.9.4330
324. Zhao, L.; Vogt, P. K. Helical Domain and Kinase Domain Mutations in p110α of Phosphatidylinositol 3-Kinase Induce Gain of Function by Different Mechanisms Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 2652-2657 10.1073/pnas.0712169105
325. Walker, E. H.; Pacold, M. E.; Perisic, O.; Stephens, L.; Hawkins, P. T.; Wymann, M. P.; Williams, R. L. Structural Determinants of Phosphoinositide 3-Kinase Inhibition by Wortmannin, LY294002, Quercetin, Myricetin, and Staurosporine Mol. Cell 2000, 6, 909-919 10.1016/S1097-2765(05)00089-4
326. Murillo, M. M.; Zelenay, S.; Nye, E.; Castellano, E.; Lassailly, F.; Stamp, G.; Downward, J. RAS Interaction with PI3K p110α Is Required for Tumor-Induced Angiogenesis J. Clin. Invest. 2014, 124, 3601-3611 10.1172/JCI74134
327. Castellano, E.; Sheridan, C.; Thin, M. Z.; Nye, E.; Spencer-Dene, B.; Diefenbacher, M. E.; Moore, C.; Kumar, M. S.; Murillo, M. M.; Grönroos, E. et al. Requirement for Interaction of PI3-Kinase p110α with RAS in Lung Tumor Maintenance Cancer Cell 2013, 24, 617-630 10.1016/j.ccr.2013.09.012
328. Gupta, S.; Ramjaun, A. R.; Haiko, P.; Wang, Y.; Warne, P. H.; Nicke, B.; Nye, E.; Stamp, G.; Alitalo, K.; Downward, J. Binding of Ras to Phosphoinositide 3-Kinase p110α Is Required for Ras-Driven Tumorigenesis in Mice Cell 2007, 129, 957-968 10.1016/j.cell.2007.03.051
329. Zhao, L.; Vogt, P. K. Hot-Spot Mutations in p110α of Phosphatidylinositol 3-Kinase (PI3K): Differential Interactions with the Regulatory Subunit p85 and with RAS Cell Cycle 2010, 9, 596-600 10.4161/cc.9.3.10599
330. Joyal, J. L.; Burks, D. J.; Pons, S.; Matter, W. F.; Vlahos, C. J.; White, M. F.; Sacks, D. B. Calmodulin Activates Phosphatidylinositol 3-Kinase J. Biol. Chem. 1997, 272, 28183-28186 10.1074/jbc.272.45.28183
331. Liao, J.; Wolfman, J. C.; Wolfman, A. K-Ras Regulates the Steady-State Expression of Matrix Metalloproteinase 2 in Fibroblasts J. Biol. Chem. 2003, 278, 31871-31878 10.1074/jbc.M301931200
332. Nussinov, R.; Muratcioglu, S.; Tsai, C.-J.; Jang, H.; Gursoy, A.; Keskin, O. K-Ras4B/Calmodulin/PI3Kα: A Promsing New Adenocarcinoma-Specific Drug Target? Expert Opin. Ther. Targets 2015, 10.1517/14728222.2016.1135131
333. Nussinov, R.; Muratcioglu, S.; Tsai, C.-J.; Jang, H.; Gursoy, A.; Keskin, O. The Key Role of Calmodulin in KRAS-Driven Adenocarcinomas Mol. Cancer Res. 2015, 13, 1265-1273 10.1158/1541-7786.MCR-15-0165
334. 13C-Methylation of Lysines to Enhance the Sensitivity of Conventional NMR Methods Molecules 2013, 18, 7103-7119 10.3390/molecules18067103
335. Xu, Y.; Li, N.; Xiang, R.; Sun, P. Emerging Roles of the p38 MAPK and PI3K/AKT/mTOR Pathways in Oncogene-Induced Senescence Trends Biochem. Sci. 2014, 39, 268-276 10.1016/j.tibs.2014.04.004
336. Aytuna, A. S.; Gursoy, A.; Keskin, O. Prediction of Protein-Protein Interactions by Combining Structure and Sequence Conservation in Protein Interfaces Bioinformatics 2005, 21, 2850-2855 10.1093/bioinformatics/bti443
337. Baspinar, A.; Cukuroglu, E.; Nussinov, R.; Keskin, O.; Gursoy, A. PRISM: A Web Server and Repository for Prediction of Protein-Protein Interactions and Modeling Their 3D Complexes Nucleic Acids Res. 2014, 42, W285-W289 10.1093/nar/gku397
338. Tuncbag, N.; Gursoy, A.; Nussinov, R.; Keskin, O. Predicting Protein-Protein Interactions on a Proteome Scale by Matching Evolutionary and Structural Similarities at Interfaces Using PRISM Nat. Protoc. 2011, 6, 1341-1354 10.1038/nprot.2011.367
339. Neel, N. F.; Martin, T. D.; Stratford, J. K.; Zand, T. P.; Reiner, D. J.; Der, C. J. The RalGEF-Ral Effector Signaling Network: The Road Less Traveled for Anti-Ras Drug Discovery Genes Cancer 2011, 2, 275-287 10.1177/1947601911407329
340. Wolthuis, R. M.; Bos, J. L. Ras Caught in Another Affair: The Exchange Factors for Ral Curr. Opin. Genet. Dev. 1999, 9, 112-117 10.1016/S0959-437X(99)80016-1
341. Ferro, E.; Trabalzini, L. RalGDS Family Members Couple Ras to Ral Signalling and That's Not All Cell. Signalling 2010, 22, 1804-1810 10.1016/j.cellsig.2010.05.010
342. Hofer, F.; Fields, S.; Schneider, C.; Martin, G. S. Activated Ras Interacts with the Ral Guanine Nucleotide Dissociation Stimulator Proc. Natl. Acad. Sci. U. S. A. 1994, 91, 11089-11093 10.1073/pnas.91.23.11089
343. Spaargaren, M.; Bischoff, J. R. Identification of the Guanine Nucleotide Dissociation Stimulator for Ral as a Putative Effector Molecule of R-Ras, H-Ras, K-Ras, and Rap Proc. Natl. Acad. Sci. U. S. A. 1994, 91, 12609-12613 10.1073/pnas.91.26.12609
344. Kikuchi, A.; Demo, S. D.; Ye, Z. H.; Chen, Y. W.; Williams, L. T. RalGDS Family Members Interact with the Effector Loop of Ras p21 Mol. Cell. Biol. 1994, 14, 7483-7491 10.1128/MCB.14.11.7483
345. Miller, M. J.; Prigent, S.; Kupperman, E.; Rioux, L.; Park, S. H.; Feramisco, J. R.; White, M. A.; Rutkowski, J. L.; Meinkoth, J. L. RalGDS Functions in Ras- and cAMP-Mediated Growth Stimulation J. Biol. Chem. 1997, 272, 5600-5605 10.1074/jbc.272.9.5600
346. González-García, A.; Pritchard, C. A.; Paterson, H. F.; Mavria, G.; Stamp, G.; Marshall, C. J. RalGDS Is Required for Tumor Formation in a Model of Skin Carcinogenesis Cancer Cell 2005, 7, 219-226 10.1016/j.ccr.2005.01.029
347. Rodriguez-Viciana, P.; McCormick, F. RalGDS Comes of Age Cancer Cell 2005, 7, 205-206 10.1016/j.ccr.2005.02.012
348. Walker, D. M.; Wang, R.; Webb, L. J. Conserved Electrostatic Fields at the Ras-Effector Interface Measured through Vibrational Stark Effect Spectroscopy Explain the Difference in Tilt Angle in the Ras Binding Domains of Raf and RalGDS Phys. Chem. Chem. Phys. 2014, 16, 20047-20060 10.1039/C4CP00743C
349. White, M. A.; Nicolette, C.; Minden, A.; Polverino, A.; Van Aelst, L.; Karin, M.; Wigler, M. H. Multiple Ras Functions can Contribute to Mammalian Cell Transformation Cell 1995, 80, 533-541 10.1016/0092-8674(95)90507-3
350. White, M. A.; Vale, T.; Camonis, J. H.; Schaefer, E.; Wigler, M. H. A Role for the Ral Guanine Nucleotide Dissociation Stimulator in Mediating Ras-Induced Transformation J. Biol. Chem. 1996, 271, 16439-16442 10.1074/jbc.271.28.16439
351. Khosravi-Far, R.; White, M. A.; Westwick, J. K.; Solski, P. A.; Chrzanowska-Wodnicka, M.; Van Aelst, L.; Wigler, M. H.; Der, C. J. Oncogenic Ras Activation of Raf/Mitogen-Activated Protein Kinase-Independent Pathways Is Sufficient to Cause Tumorigenic Transformation Mol. Cell. Biol. 1996, 16, 3923-3933 10.1128/MCB.16.7.3923
352. Joneson, T.; White, M. A.; Wigler, M. H.; Bar-Sagi, D. Stimulation of Membrane Ruffling and MAP Kinase Activation by Distinct Effectors of RAS Science 1996, 271, 810-812 10.1126/science.271.5250.810
353. Okazaki, M.; Kishida, S.; Hinoi, T.; Hasegawa, T.; Tamada, M.; Kataoka, T.; Kikuchi, A. Synergistic Activation of c-Fos Promoter Activity by Raf and Ral GDP Dissociation Stimulator Oncogene 1997, 14, 515-521 10.1038/sj.onc.1200860
354. Hwang, M. C.; Sung, Y. J.; Hwang, Y. W. The Differential Effects of the Gly-60 to Ala Mutation on the Interaction of H-Ras p21 with Different Downstream Targets J. Biol. Chem. 1996, 271, 8196-8202 10.1074/jbc.271.14.8196
355. Wang, Y. A. N.; Xu, H.; Riggs, M.; Rodgers, L.; Wigler, M. byr2, a Schizosaccharomyces Pombe Gene Encoding a Protein Kinase Capable of Partial Suppression of the Rasi Mutant Phenotype Mol. Cell. Biol. 1991, 11, 3554-3563 10.1128/MCB.11.7.3554
356. Xu, H. P.; White, M.; Marcus, S.; Wigler, M. Concerted Action of RAS and G Proteins in the Sexual Response Pathways of Schizosaccharomyces Pombe Mol. Cell. Biol. 1994, 14, 50-58 10.1128/MCB.14.1.50
357. Onken, B.; Wiener, H.; Philips, M. R.; Chang, E. C. Compartmentalized Signaling of Ras in Fission Yeast Proc. Natl. Acad. Sci. U. S. A. 2006, 103, 9045-9050 10.1073/pnas.0603318103
358. Papadaki, P.; Pizon, V.; Onken, B.; Chang, E. C. Two Ras Pathways in Fission Yeast Are Differentially Regulated by Two Ras Guanine Nucleotide Exchange Factors Mol. Cell. Biol. 2002, 22, 4598-4606 10.1128/MCB.22.13.4598-4606.2002
359. Bauman, P.; Albright, C. F. Functional Analysis of Domains in the Byr2 Kinase Biochimie 1998, 80, 621-625 10.1016/S0300-9084(98)80015-1
360. Tu, H.; Barr, M.; Dong, D. L.; Wigler, M. Multiple Regulatory Domains on the Byr2 Protein Kinase Mol. Cell. Biol. 1997, 17, 5876-5887 10.1128/MCB.17.10.5876
361. Masuda, T.; Kariya, K.; Shinkai, M.; Okada, T.; Kataoka, T. Protein Kinase Byr2 Is a Target of Ras1 in the Fission Yeast Schizosaccharomyces Pombe J. Biol. Chem. 1995, 270, 1979-1982 10.1074/jbc.270.5.1979
362. Fabian, J. R.; Vojtek, A. B.; Cooper, J. A.; Morrison, D. K. A Single Amino Acid Change in Raf-1 Inhibits Ras Binding and Alters Raf-1 Function Proc. Natl. Acad. Sci. U. S. A. 1994, 91, 5982-5926 10.1073/pnas.91.13.5982
363. Smrcka, A. V.; Brown, J. H.; Holz, G. G. Role of Phospholipase C in Physiological Phosphoinositide Signaling Networks Cell. Signalling 2012, 24, 1333-1343 10.1016/j.cellsig.2012.01.009
364. Rhee, S. G. Regulation of Phosphoinositide-Specific Phospholipase C Annu. Rev. Biochem. 2001, 70, 281-312 10.1146/annurev.biochem.70.1.281
365. Ponting, C. P.; Benjamin, D. R. A Novel Family of Ras-Binding Domains Trends Biochem. Sci. 1996, 21, 422-425 10.1016/S0968-0004(96)30038-8
366. Wing, M. R.; Houston, D.; Kelley, G. G.; Der, C. J.; Siderovski, D. P.; Harden, T. K. Activation of Phospholipase C-Epsilon by Heterotrimeric G Protein β -Subunits J. Biol. Chem. 2001, 276, 48257-48261
367. McCudden, C. R.; Hains, M. D.; Kimple, R. J.; Siderovski, D. P.; Willard, F. S. G-Protein Signaling: Back to the Future Cell. Mol. Life Sci. 2005, 62, 551-577 10.1007/s00018-004-4462-3
368. Bunney, T. D.; Katan, M. Phospholipase C Epsilon: Linking Second Messengers and Small GTPases Trends Cell Biol. 2006, 16, 640-648 10.1016/j.tcb.2006.10.007
369. Kelley, G. G.; Reks, S. E.; Ondrako, J. M.; Smrcka, A. V. Phospholipase C: A Novel Ras Effector EMBO J. 2001, 20, 743-754 10.1093/emboj/20.4.743
370. Martins, M.; McCarthy, A.; Baxendale, R.; Guichard, S.; Magno, L.; Kessaris, N.; El-Bahrawy, M.; Yu, P.; Katan, M. Tumor Suppressor Role of Phospholipase C in Ras-Triggered Cancers Proc. Natl. Acad. Sci. U. S. A. 2014, 111, 4239-4244 10.1073/pnas.1311500111
371. Harris, R.; Bunney, T. D.; Katan, M.; Driscoll, P. C. Backbone 1H, 13C, and 15N Resonance Assignments for the Two 13 kD Ras Associating Domains (RA1 and RA2) from Phospholipase C Epsilon J. Biomol. NMR 2005, 33, 138 10.1007/s10858-005-3094-0
372. Gandarillas, N. L.; Bunney, T. D.; Josephs, M. B.; Gierschik, P.; Katan, M. In Vitro Reconstitution of Activation of PLC by Ras and Rho GTPases Methods Mol. Biol. 2009, 462, 379-389 10.1007/978-1-60327-115-8-24
373. Seifert, J. P.; Zhou, Y.; Hicks, S. N.; Sondek, J.; Harden, T. K. Dual Activation of Phospholipase C by Rho and Ras GTPases J. Biol. Chem. 2008, 283, 29690-29698 10.1074/jbc.M805038200
374. Bunney, T. D.; Katan, M. PLC Regulation: Emerging Pictures for Molecular Mechanisms Trends Biochem. Sci. 2011, 36, 88-96 10.1016/j.tibs.2010.08.003
375. Hicks, S. N.; Jezyk, M. R.; Gershburg, S.; Seifert, J. P.; Harden, T. K.; Sondek, J. General and Versatile Autoinhibition of PLC Isozymes Mol. Cell 2008, 31, 383-394 10.1016/j.molcel.2008.06.018
376. Song, C.; Hu, C. D.; Masago, M.; Kariya, K.-i.; Yamawaki-Kataoka, Y.; Shibatohge, M.; Wu, D.; Satoh, T.; Kataoka, T. Regulation of a Novel Human Phospholipase C, PLC, through Membrane Targeting by Ras J. Biol. Chem. 2001, 276, 2752-2757 10.1074/jbc.M008324200
377. Edamatsu, H.; Satoh, T.; Kataoka, T. Ras and Rap1 Activation of PLC Lipase Activity Methods Enzymol. 2006, 407, 99-107 10.1016/S0076-6879(05)07009-6
378. Harden, T. K.; Sondek, J. Regulation of Phospholipase C Isozymes by Ras Superfamily GTPases Annu. Rev. Pharmacol. Toxicol. 2006, 46, 355-379 10.1146/annurev.pharmtox.46.120604.141223
379. Wing, M. R.; Snyder, J. T.; Sondek, J.; Harden, T. K. Direct Activation of Phospholipase C by Rho J. Biol. Chem. 2003, 278, 41253-41258 10.1074/jbc.M306904200
380. Sorli, S. C.; Bunney, T. D.; Sugden, P. H.; Paterson, H. F.; Katan, M. Signaling Properties and Expression in Normal and Tumor Tissues of Two Phospholipase C Splice Variants Oncogene 2005, 24, 90-100 10.1038/sj.onc.1208168
381. Bunney, T. D.; Baxendale, R. W.; Katan, M. Regulatory Links between PLC Enzymes and Ras Superfamily GTPases: Signalling via PLC Adv. Enzyme Regul. 2009, 49, 54-58 10.1016/j.advenzreg.2009.01.004
382. Hesson, L.; Dallol, A.; Minna, J. D.; Maher, E. R.; Latif, F. NORE1A, a Homologue of RASSF1A Tumour Suppressor Gene Is Inactivated in Human Cancers Oncogene 2003, 22, 947-954 10.1038/sj.onc.1206191
383. Avruch, J.; Praskova, M.; Ortiz-Vega, S.; Liu, M.; Zhang, X.-F. Nore1 and RASSF1 Regulation of Cell Proliferation and of the MST1/2 Kinases Methods Enzymol. 2006, 407, 290-310 10.1016/S0076-6879(05)07025-4
384. Makbul, C.; Constantinescu Aruxandei, D.; Hofmann, E.; Schwarz, D.; Wolf, E.; Herrmann, C. Structural and Thermodynamic Characterization of Nore1-SARAH: A Small, Helical Module Important in Signal Transduction Networks Biochemistry 2013, 52, 1045-1054 10.1021/bi3014642
385. Praskova, M.; Khoklatchev, A.; Ortiz-Vega, S.; Avruch, J. Regulation of the MST1 Kinase by Autophosphorylation, by the Growth Inhibitory Proteins, RASSF1 and NORE1, and by Ras Biochem. J. 2004, 381, 453-462 10.1042/BJ20040025
386. Bee, C.; Moshnikova, A.; Mellor, C. D.; Molloy, J. E.; Koryakina, Y.; Stieglitz, B.; Khokhlatchev, A.; Herrmann, C. Growth and Tumor Suppressor NORE1A Is a Regulatory Node between Ras Signaling and Microtubule Nucleation J. Biol. Chem. 2010, 285, 16258-16266 10.1074/jbc.M109.081562
387. Donninger, H.; Calvisi, D. F.; Barnoud, T.; Clark, J.; Schmidt, M. L.; Vos, M. D.; Clark, G. J. NORE1A Is a Ras Senescence Effector That Controls the Apoptotic/senescent Balance of p53 via HIPK2 J. Cell Biol. 2015, 208, 777-789 10.1083/jcb.201408087
388. Schmidt, M. L.; Donninger, H.; Clark, G. J. Ras Regulates SCF -TrCP Protein Activity and Specificity via Its Effector Protein NORE1A J. Biol. Chem. 2014, 289, 31102-31110 10.1074/jbc.M114.594283
389. Vavvas, D.; Li, X.; Avruch, J.; Zhang, X. F. Identification of Nore1 as a Potential Ras Effector J. Biol. Chem. 1998, 273, 5439-5442 10.1074/jbc.273.10.5439
390. Wohlgemuth, S.; Kiel, C.; Krämer, A.; Serrano, L.; Wittinghofer, F.; Herrmann, C. Recognizing and Defining True Ras Binding Domains I: Biochemical Analysis J. Mol. Biol. 2005, 348, 741-758 10.1016/j.jmb.2005.02.048
391. Vos, M. D.; Martinez, A.; Ellis, C. A.; Vallecorsa, T.; Clark, G. J. The pro-Apoptotic Ras Effector Nore1May Serve as a Ras-Regulated Tumor Suppressor in the Lung J. Biol. Chem. 2003, 278, 21938-21943 10.1074/jbc.M211019200
392. Gupta, V. K.; Rajala, A.; Rajala, R. V. S. Ras-Associating Domain Proteins: A New Class of Cyclic Nucleotide-Gated Channel Modulators Adv. Exp. Med. Biol. 2012, 723, 777-782 10.1007/978-1-4614-0631-0-99
393. Rajala, R. V. S.; Rajala, A.; Gupta, V. K. Conservation and Divergence of Grb7 Family of Ras-Binding Domains Protein Cell 2012, 3, 60-70 10.1007/s13238-012-2001-1
394. Wojcik, J.; Girault, J. A.; Labesse, G.; Chomilier, J.; Mornon, J. P.; Callebaut, I. Sequence Analysis Identifies a Ras-Associating (RA)-like Domain in the N-Termini of Band 4.1/JEF Domains and in the Grb7/10/14 Adapter Family Biochem. Biophys. Res. Commun. 1999, 259, 113-120 10.1006/bbrc.1999.0727
395. Kabir, N. N.; Kazi, J. U. Grb10 Is a Dual Regulator of Receptor Tyrosine Kinase Signaling Mol. Biol. Rep. 2014, 41, 1985-1992 10.1007/s11033-014-3046-4
396. Gupta, V. K.; Rajala, A.; Rodgers, K. K.; Rajala, R. V. S. Mechanism Involved in the Modulation of Photoreceptor-Specific Cyclic Nucleotidegated Channel by the Tyrosine Kinase Adapter Protein Grb14 Protein Cell 2011, 2, 906-917 10.1007/s13238-011-1115-1
397. Gupta, V. K.; Rajala, A.; Daly, R. J.; Rajala, R. V. S. Growth Factor Receptor-Bound Protein 14: A New Modulator of Photoreceptor-Specific Cyclic-Nucleotide-Gated Channel EMBO Rep. 2010, 11, 861-867 10.1038/embor.2010.142
398. Depetris, R. S.; Hu, J.; Gimpelevich, I.; Holt, L. J.; Daly, R. J.; Hubbard, S. R. Structural Basis for Inhibition of the Insulin Receptor by the Adaptor Protein Grb14 Mol. Cell 2005, 20, 325-333 10.1016/j.molcel.2005.09.001
399. Cooney, G. J.; Lyons, R. J.; Crew, A. J.; Jensen, T. E.; Molero, J. C.; Mitchell, C. J.; Biden, T. J.; Ormandy, C. J.; James, D. E.; Daly, R. J. Improved Glucose Homeostasis and Enhanced Insulin Signalling in Grb14-Deficient Mice EMBO J. 2004, 23, 582-593 10.1038/sj.emboj.7600082
400. Béréziat, V.; Kasus-Jacobi, A.; Perdereau, D.; Cariou, B.; Girard, J.; Burnol, A.-F. Inhibition of Insulin Receptor Catalytic Activity by the Molecular Adapter Grb14 J. Biol. Chem. 2002, 277, 4845-4852 10.1074/jbc.M106574200
401. Depetris, R. S.; Wu, J.; Hubbard, S. R. Structural and Functional Studies of the Ras-Associating and Pleckstrin-Homology Domains of Grb10 and Grb14 Nat. Struct. Mol. Biol. 2009, 16, 833-839 10.1038/nsmb.1642
402. Kiel, C.; Selzer, T.; Shaul, Y.; Schreiber, G.; Herrmann, C. Electrostatically Optimized Ras-Binding Ral Guanine Dissociation Stimulator Mutants Increase the Rate of Association by Stabilizing the Encounter Complex Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 9223-9228 10.1073/pnas.0401160101
403. Güldenhaupt, J.; Rudack, T.; Bachler, P.; Mann, D.; Triola, G.; Waldmann, H.; Kötting, C.; Gerwert, K. N-Ras Forms Dimers at POPC Membranes Biophys. J. 2012, 103, 1585-1593 10.1016/j.bpj.2012.08.043
404. Lin, W.-C.; Iversen, L.; Tu, H.-L.; Rhodes, C.; Christensen, S. M.; Iwig, J. S.; Hansen, S. D.; Huang, W. Y. C.; Groves, J. T. H-Ras Forms Dimers on Membrane Surfaces via a Protein-Protein Interface Proc. Natl. Acad. Sci. U. S. A. 2014, 111, 2996-3001 10.1073/pnas.1321155111
405. Jambrina, P. G.; Bohuszewicz, O.; Buchete, N.-V.; Kolch, W.; Rosta, E. Molecular Mechanisms of Asymmetric RAF Dimer Activation Biochem. Soc. Trans. 2014, 42, 784-790 10.1042/BST20140025
406. Inouye, K.; Mizutani, S.; Koide, H.; Kaziro, Y. Formation of the Ras Dimer Is Essential for Raf-1 Activation J. Biol. Chem. 2000, 275, 3737-3740 10.1074/jbc.275.6.3737
407. Nan, X.; Tamgüney, T. M.; Collisson, E. A.; Lin, L.-J.; Pitt, C.; Galeas, J.; Lewis, S.; Gray, J. W.; McCormick, F.; Chu, S. Ras-GTP Dimers Activate the Mitogen-Activated Protein Kinase (MAPK) Pathway Proc. Natl. Acad. Sci. U. S. A. 2015, 112, 7996-8001 10.1073/pnas.1509123112
408. Philips, M. R.; Der, C. J. Seeing Is Believing: Ras Dimers Observed in Live Cells Proc. Natl. Acad. Sci. U. S. A. 2015, 112, 9793-9794 10.1073/pnas.1511805112
409. Muratcioglu, S.; Chavan, T. S.; Freed, B. C.; Jang, H.; Khavrutskii, L.; Freed, R. N.; Dyba, M. A.; Stefanisko, K.; Tarasov, S. G.; Gursoy, A. et al. GTP-Dependent K-Ras Dimerization Structure 2015, 23, 1325-1335 10.1016/j.str.2015.04.019
410. 31P NMR Spectroscopy FEBS Lett. 2004, 578, 305-310 10.1016/j.febslet.2004.11.020
411. Prior, I. A.; Muncke, C.; Parton, R. G.; Hancock, J. F. Direct Visualization of Ras Proteins in Spatially Distinct Cell Surface Microdomains J. Cell Biol. 2003, 160, 165-170 10.1083/jcb.200209091
412. Hibino, K.; Watanabe, T. M.; Kozuka, J.; Iwane, A. H.; Okada, T.; Kataoka, T.; Yanagida, T.; Sako, Y. Single- and Multiple-Molecule Dynamics of the Signaling from H-Ras to cRaf-1 Visualized on the Plasma Membrane of Living Cells ChemPhysChem 2003, 4, 748-753 10.1002/cphc.200300731
413. Murakoshi, H.; Iino, R.; Kobayashi, T.; Fujiwara, T.; Ohshima, C.; Yoshimura, A.; Kusumi, A. Single-Molecule Imaging Analysis of Ras Activation in Living Cells Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 7317-7322 10.1073/pnas.0401354101
414. Plowman, S. J.; Muncke, C.; Parton, R. G.; Hancock, J. F. H-Ras, K-Ras, and Inner Plasma Membrane Raft Proteins Operate in Nanoclusters with Differential Dependence on the Actin Cytoskeleton Proc. Natl. Acad. Sci. U. S. A. 2005, 102, 15500-15505 10.1073/pnas.0504114102
415. Nussinov, R.; Jang, H. Dynamic Multiprotein Assemblies Shape the Spatial Structure of Cell Signaling Prog. Biophys. Mol. Biol. 2014, 116, 158-164 10.1016/j.pbiomolbio.2014.07.002
416. Nussinov, R. The Spatial Structure of Cell Signaling Systems Phys. Biol. 2013, 10, 045004 10.1088/1478-3975/10/4/045004
417. Zhou, Y.; Liang, H.; Rodkey, T.; Ariotti, N.; Parton, R. G.; Hancock, J. F. Signal Integration by Lipid-Mediated Spatial Cross Talk between Ras Nanoclusters Mol. Cell. Biol. 2014, 34, 862-876 10.1128/MCB.01227-13
418. Li, H.; Gorfe, A. A. Aggregation of Lipid-Anchored Full-Length H-Ras in Lipid Bilayers: Simulations with the MARTINI Force Field PLoS One 2013, 8, e71018 10.1371/journal.pone.0071018
419. Shalom-Feuerstein, R.; Plowman, S. J.; Rotblat, B.; Ariotti, N.; Tian, T.; Hancock, J. F.; Kloog, Y. K-Ras Nanoclustering Is Subverted by Overexpression of the Scaffold Protein Galectin-3 Cancer Res. 2008, 68, 6608-6616 10.1158/0008-5472.CAN-08-1117
420. Tian, T.; Plowman, S. J.; Parton, R. G.; Kloog, Y.; Hancock, J. F. Mathematical Modeling of K-Ras Nanocluster Formation on the Plasma Membrane Biophys. J. 2010, 99, 534-543 10.1016/j.bpj.2010.04.055
421. Eisenberg, S.; Henis, Y. I. Interactions of Ras Proteins with the Plasma Membrane and Their Roles in Signaling Cell. Signalling 2008, 20, 31-39 10.1016/j.cellsig.2007.07.012
422. ras to the Plasma Membrane Cell 1990, 63, 133-139 10.1016/0092-8674(90)90294-O
423. Tsai, F. D.; Lopes, M. S.; Zhou, M.; Court, H.; Ponce, O.; Fiordalisi, J. J.; Gierut, J. J.; Cox, A. D.; Haigis, K. M.; Philips, M. R. K-Ras4A Splice Variant Is Widely Expressed in Cancer and Uses a Hybrid Membrane-Targeting Motif Proc. Natl. Acad. Sci. U. S. A. 2015, 112, 779-784 10.1073/pnas.1412811112
424. Gorfe, A. A.; Babakhani, A.; Mccammon, J. A. H-Ras Protein in a Bilayer: Interaction and Structure Perturbation J. Am. Chem. Soc. 2007, 129, 12280-12286 10.1021/ja073949v
425. Vogel, A.; Reuther, G.; Roark, M. B.; Tan, K.; Waldmann, H.; Feller, S. E.; Huster, D. Biochimica et Biophysica Acta Backbone Conformational Fl Exibility of the Lipid Modi Fi Ed Membrane Anchor of the Human N-Ras Protein Investigated by Solid-State NMR and Molecular Dynamics Simulation Biochim. Biophys. Acta, Biomembr. 2010, 1798, 275-285 10.1016/j.bbamem.2009.09.023
426. Janosi, L.; Gorfe, A. A. Segregation of Negatively Charged Phospholipids by the Polycationic and Farnesylated Membrane Anchor of Kras Biophys. J. 2010, 99, 3666-3674 10.1016/j.bpj.2010.10.031
427. Pike, L. J. The Challenge of Lipid Rafts J. Lipid Res. 2009, 50, S323-S328 10.1194/jlr.R800040-JLR200
428. Anchisi, L.; Dessì, S.; Pani, A.; Mandas, A. Cholesterol Homeostasis: A Key to Prevent or Slow down Neurodegeneration Front. Physiol. 2013, 3, 486 10.3389/fphys.2012.00486
429. Laude, A. J.; Prior, I. A. Plasma Membrane Microdomains: Organization, Function and Trafficking Mol. Membr. Biol. 2004, 21, 193-205 10.1080/09687680410001700517
430. Janes, P. W.; Ley, S. C.; Magee, A. I.; Kabouridis, P. S. The Role of Lipid Rafts in T Cell Antigen Receptor (TCR) signalling Semin. Immunol. 2000, 12, 23-34 10.1006/smim.2000.0204
431. Simons, K.; Vaz, W. L. C. Model Systems, Lipid Rafts,and Cell Membranes Annu. Rev. Biophys. Biomol. Struct. 2004, 33, 269-295 10.1146/annurev.biophys.32.110601.141803
432. Rizzo, M. A.; Kraft, C. A.; Watkins, S. C.; Levitan, E. S.; Romero, G. Agonist-Dependent Traffic of Raft-Associated Ras and Raf-1 Is Required for Activation of the Mitogen-Activated Protein Kinase J. Biol. Chem. 2001, 276, 34928-34933 10.1074/jbc.M105918200
433. Mineo, C.; James, G. L.; Smart, E. J.; Anderson, R. G. W. Localization of Epidermal Growth Factor-Stimulated Ras/Raf-1 Interaction to Caveolae Membrane J. Biol. Chem. 1996, 271, 11930-11935 10.1074/jbc.271.20.11930
434. Prior, I. A.; Hancock, J. F. Compartmentalization of Ras Proteins J. Cell Sci. 2001, 114, 1603-1608
435. Niv, H.; Gutman, O.; Kloog, Y.; Henis, Y. I. Activated K-Ras and H-Ras Display Different Interactions with Saturable Nonraft Sites at the Surface of Live Cells J. Cell Biol. 2002, 157, 865-872 10.1083/jcb.200202009
436. Weise, K.; Kapoor, S.; Denter, C.; Nikolaus, J.; Opitz, N.; Koch, S.; Triola, G.; Herrmann, A.; Waldmann, H.; Winter, R. Membrane-Mediated Induction and Sorting of K-Ras Microdomain Signaling Platforms J. Am. Chem. Soc. 2011, 133, 880-887 10.1021/ja107532q
437. Furuchi, T.; Anderson, R. G. W. Cholesterol Depletion of Caveolae Causes Hyperactivation of Extracellular Signal-Related Kinase (ERK) J. Biol. Chem. 1998, 273, 21099-21104 10.1074/jbc.273.33.21099
438. White, M. A.; Anderson, R. G. W. Which Ras Rides the Raft? Nat. Cell Biol. 2001, 3, E172 10.1038/35087098
439. Zhou, Y.; Wong, C.-O.; Cho, K.; van der Hoeven, D.; Liang, H.; Thakur, D. P.; Luo, J.; Babic, M.; Zinsmaier, K. E.; Zhu, M. X. et al. SIGNAL TRANSDUCTION. Membrane Potential Modulates Plasma Membrane Phospholipid Dynamics and K-Ras Signaling Science 2015, 349, 873-876 10.1126/science.aaa5619
440. Abankwa, D.; Gorfe, A. A.; Inder, K.; Hancock, J. F. Ras Membrane Orientation and Nanodomain Localization Generate Isoform Diversity Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 1130-1135 10.1073/pnas.0903907107
441. Gorfe, A. A.; Hanzal-bayer, M.; Abankwa, D.; Hancock, J. F.; Mccammon, J. A. Structure and Dynamics of the Full-Length Lipid-Modified H-Ras Protein in a 1,2-Dimyristoylglycero-3-Phosphocholine Bilayer J. Med. Chem. 2007, 50, 674-684 10.1021/jm061053f
442. Jang, H.; Banerjee, A.; Chavan, T. S.; Lu, S.; Zhang, J.; Gaponenko, V.; Nussinov, R. The Higher Level of Complexity of K-Ras4B Activation at the Membrane FASEB J. 2015, 10.1096/fj.15-279091
443. Krishnamurthy, S.; Tulsian, N. K.; Chandramohan, A.; Anand, G. S. Parallel Allostery by cAMP and PDE Coordinates Activation and Termination Phases in cAMP Signaling Biophys. J. 2015, 109, 1251-1263 10.1016/j.bpj.2015.06.067
444. Pontiggia, F.; Pachov, D. V.; Clarkson, M. W.; Villali, J.; Hagan, M. F.; Pande, V. S.; Kern, D. Free Energy Landscape of Activation in a Signalling Protein at Atomic Resolution Nat. Commun. 2015, 6, 7284 10.1038/ncomms8284
445. Kerns, S. J.; Agafonov, R. V.; Cho, Y.-J.; Pontiggia, F.; Otten, R.; Pachov, D. V.; Kutter, S.; Phung, L. A.; Murphy, P. N.; Thai, V. et al. The Energy Landscape of Adenylate Kinase during Catalysis Nat. Struct. Mol. Biol. 2015, 22, 124-131 10.1038/nsmb.2941
446. Nussinov, R.; Tsai, C.-J.; Ma, B. The Underappreciated Role of Allostery in the Cellular Network Annu. Rev. Biophys. 2013, 42, 169-189 10.1146/annurev-biophys-083012-130257
447. Jenik, M.; Parra, R. G.; Radusky, L. G.; Turjanski, A.; Wolynes, P. G.; Ferreiro, D. U. Protein Frustratometer: A Tool to Localize Energetic Frustration in Protein Molecules Nucleic Acids Res. 2012, 40, W348-W351 10.1093/nar/gks447
448. Nussinov, R.; Tsai, C.-J. Free Energy Diagrams for Protein Function Chem. Biol. 2014, 21, 311-318 10.1016/j.chembiol.2013.12.015
449. Lu, S.; Deng, R.; Jiang, H.; Song, H.; Li, S.; Shen, Q.; Huang, W.; Nussinov, R.; Yu, J.; Zhang, J. The Mechanism of ATP-Dependent Allosteric Protection of Akt Kinase Phosphorylation Structure 2015, 23, 1725-1734 10.1016/j.str.2015.06.027
450. Solman, M.; Ligabue, A.; Blazevits, O.; Jaiswal, A.; Zhou, Y.; Liang, H.; Lectez, B.; Kopra, K.; Guzman, C.; Härmä, H. et al. Specific Cancer Associated Mutations in the Switch III-Region of Ras Increase Tumorigenicity by Nanocluster Augmentation eLife 2015, 4, e08905 10.7554/eLife.08905
451. Kumar, A.; Glembo, T. J.; Ozkan, S. B. The Role of Conformational Dynamics and Allostery in the Disease Development of Human Ferritin Biophys. J. 2015, 109, 1273-1281 10.1016/j.bpj.2015.06.060
452. Shehu, A.; Nussinov, R. Computational Methods for Exploration and Analysis of Macromolecular Structure and Dynamics PLoS Comput. Biol. 2015, 11, e1004585 10.1371/journal.pcbi.1004585
453. Clausen, R.; Ma, B.; Nussinov, R.; Shehu, A. Mapping the Conformational Space of Wildtype and Mutant H-Ras with a Memetic, Cellular, and Multiscale Evolutionary Algorithm PLoS Comput. Biol. 2015, 11, e1004470 10.1371/journal.pcbi.1004470
454. Cromm, P. M.; Spiegel, J.; Grossmann, T. N.; Waldmann, H. Direct Modulation of Small GTPase Activity and Function Angew. Chem.; Int. Ed. 2015, 54, 13516-13537 10.1002/anie.201504357
455. Nussinov, R.; Tsai, C.-J.; Muratcioglu, S.; Jang, H.; Gursoy, A.; Keskin, O. Principles of K-Ras Effector Organization and the Role of Oncogenic K-Ras in Cancer Initiation through G1 Cell Cycle Deregulation Expert Rev. Proteomics 2015, 12, 669-682 10.1586/14789450.2015.1100079
456. Banerjee, A.; Jang, H.; Nussinov, R.; Gaponenko, V. The Disordered Hypervariable Region and the Folded Catalytic Domain of Oncogenic K-Ras4B Partner in Phospholipid Binding Curr. Opin. Struct. Biol. 2016, 36, 10-17 10.1016/j.sbi.2015.11.010