MTOR kinase structure, mechanism and regulation

Nature

Volumn 497, Issue 7448, 2013, Pages 217-223

  Yang, Haijuan ^a   Rudge, Derek G ^a   Koos, Joseph D ^a   Vaidialingam, Bhamini ^a   Yang, Hyo J ^a   Pavletich, Nikola P ^a  

^a MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 (4 AMINO 1 ISOPROPYL 1H PYRAZOLO[3,4 D]PYRIMIDIN 3 YL) 1H INDOL 5 OL; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; PHOSPHATIDYLINOSITOL 3 KINASE;

CANCER; CATALYSIS; CRYSTAL STRUCTURE; ENZYME ACTIVITY; INHIBITOR; MAMMAL; PROTEIN;

ARTICLE; BINDING SITE; CONFORMATIONAL TRANSITION; DEPHOSPHORYLATION; HUMAN; HYDROGEN BOND; IN VITRO STUDY; IN VIVO STUDY; MUTATION; NUCLEOPHILICITY; PHENOTYPE; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN CONFORMATION; PROTEIN PHOSPHORYLATION; PROTEIN STRUCTURE; X RAY DIFFRACTION;

ADAPTOR PROTEINS, SIGNAL TRANSDUCING; ADENOSINE TRIPHOSPHATE; CATALYTIC DOMAIN; CRYSTALLOGRAPHY, X-RAY; FURANS; HUMANS; INDOLES; MAGNESIUM; MODELS, MOLECULAR; NAPHTHYRIDINES; PROTEIN STRUCTURE, TERTIARY; PURINES; PYRIDINES; PYRIMIDINES; RIBOSOMAL PROTEIN S6 KINASES, 70-KDA; SIROLIMUS; STRUCTURE-ACTIVITY RELATIONSHIP; TACROLIMUS BINDING PROTEIN 1A; TOR SERINE-THREONINE KINASES;

MAMMALIA; PYRONIA TITHONUS;

EID: 84877761058     PISSN: 00280836     EISSN: 14764687     Source Type: Journal    
DOI: 10.1038/nature12122     Document Type: Article

References (53)

1. Zoncu, R., Efeyan, A. & Sabatini, D. M. mTOR: from growth signal integration to cancer, diabetes and ageing. Nature Rev. Mol. Cell Biol. 12, 21-35 (2011).
2. Shaw, R. J. & Cantley, L. C. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 441, 424-430 (2006).
3. Keith, C. T. & Schreiber, S. L. PIK-related kinases: DNA repair, recombination, and cell cycle checkpoints. Science 270, 50-51 (1995).
4. Hara, K. et al.Raptor, a binding partner of target of rapamycin (TOR),mediatesTOR action. Cell 110, 177-189 (2002).
5. Kim, D. H. et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110, 163-175 (2002).
6. Loewith, R. et al. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol. Cell 10, 457-468 (2002).
7. Sarbassov, D. D. et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 14, 1296-1302 (2004).
8. Chen, E. J. & Kaiser, C. A. LST8 negatively regulates amino acid biosynthesis as a component of the TOR pathway. J. Cell Biol. 161, 333-347 (2003).
9. Kim, D. H. et al. GbL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol. Cell 11, 895-904 (2003).
10. Sancak, Y. et al. The Rag GTPases bind raptor andmediateamino acid signaling to mTORC1. Science 320, 1496-1501 (2008).
11. Kim, E., Goraksha-Hicks, P., Li, L., Neufeld, T. P. & Guan, K. L. Regulation of TORC1 by Rag GTPases in nutrient response. Nature Cell Biol. 10, 935-945 (2008).
12. Saucedo, L. J. et al. Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nature Cell Biol. 5, 566-571 (2003).
13. Stocker, H. et al. Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. Nature Cell Biol. 5, 559-566 (2003).
14. Long, X., Lin, Y., Ortiz-Vega, S., Yonezawa, K. & Avruch, J. Rheb binds and regulates the mTOR kinase. Curr. Biol. 15, 702-713 (2005).
15. Sato, T., Nakashima, A., Guo, L. & Tamanoi, F. Specific activation of mTORC1 by Rheb G-protein in vitro involves enhanced recruitment of its substrate protein. J. Biol. Chem. 284, 12783-12791 (2009).
16. Sancak, Y. et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol. Cell 25, 903-915 (2007).
17. Zhang, Y. et al. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nature Cell Biol. 5, 578-581 (2003).
18. Ma, X. M. & Blenis, J. Molecular mechanisms of mTOR-mediated translational control. Nature Rev. Mol. Cell Biol. 10, 307-318 (2009).
19. Schalm, S. S., Fingar, D. C., Sabatini, D. M. & Blenis, J. TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function. Curr. Biol. 13, 797-806 (2003).
20. Nojima, H. et al. The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif. J. Biol. Chem. 278, 15461-15464 (2003).
21. Oshiro, N. et al. The proline-rich Akt substrate of 40 kDa (PRAS40) is a physiological substrate of mammalian target of rapamycin complex 1. J. Biol. Chem. 282, 20329-20339 (2007).
22. Fonseca, B. D., Smith, E. M., Lee, V. H., MacKintosh, C. & Proud, C. G. PRAS40 is a target for mammalian target of rapamycin complex 1 and is required for signaling downstream of this complex. J. Biol. Chem. 282, 24514-24524 (2007).
23. Jacinto, E. et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nature Cell Biol. 6, 1122-1128 (2004).
24. Choi, J., Chen, J., Schreiber, S. L. & Clardy, J. Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP. Science 273, 239-242 (1996).
25. Choo, A. Y. & Blenis, J. Not all substrates are treated equally: implications for mTOR, rapamycin-resistance and cancer therapy. Cell Cycle 8, 567-572 (2009).
26. Wander, S. A., Hennessy, B. T. & Slingerland, J. M.Next- generationmTORinhibitors in clinical oncology: how pathway complexity informs therapeutic strategy. J. Clin. Invest. 121, 1231-1241 (2011).
27. Lovejoy, C. A. & Cortez, D. Common mechanisms of PIKK regulation. DNA Repair (Amst.) 8, 1004-1008 (2009).
28. Bosotti, R., Isacchi, A. & Sonnhammer, E. L. FAT: a novel domain in PIK-related kinases. Trends Biochem. Sci. 25, 225-227 (2000).
29. Walker, E. H., Perisic, O., Ried, C., Stephens, L. & Williams, R. L. Structural insights into phosphoinositide 3-kinase catalysis and signalling. Nature 402, 313-320 (1999).
30. Sibanda, B. L., Chirgadze, D. Y. & Blundell, T. L. Crystal structure of DNA-PKcs reveals a large open-ring cradle comprised ofHEAT repeats.Nature 463, 118-121 (2010).
31. Nolen, B., Taylor, S. & Ghosh, G. Regulation of protein kinases; controlling activity through activation segment conformation. Mol. Cell 15, 661-675 (2004).
32. Miller, S. et al. Shaping development of autophagy inhibitors with the structure of the lipid kinase Vps34. Science 327, 1638-1642 (2010).
33. McMahon, L. P., Choi, K. M., Lin, T. A., Abraham, R. T. & Lawrence, J. C. Jr. The rapamycin-binding domain governs substrate selectivity by the mammalian target of rapamycin. Mol. Cell. Biol. 22, 7428-7438 (2002).
34. Sekulic, A. et al. A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and themammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res. 60, 3504-3513 (2000).
35. Edinger, A. L. & Thompson, C. B. An activated mTOR mutant supports growth factor-independent, nutrient-dependent cell survival. Oncogene 23, 5654-5663 (2004).
36. Bao, Z. Q., Jacobsen, D. M. & Young, M. A. Briefly bound to activate: transient binding of a second catalytic magnesiumactivates the structure and dynamics of CDK2 kinase for catalysis. Structure 19, 675-690 (2011).
37. Madhusudan, A. P. Xuong, N. H.& Taylor, S. S. Crystal structure of a transition state mimic of the catalytic subunit of cAMP-dependent protein kinase. Nature Struct. Biol. 9, 273-277 (2002).
38. Brown, E. J. et al. Control of p70 s6 kinase by kinase activity of FRAP in vivo. Nature 377, 441-446 (1995).
39. Hsu, P. P. et al. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science 332, 1317-1322 (2011).
40. Vilella-Bach, M., Nuzzi, P., Fang, Y. & Chen, J. The FKBP12-rapamycin-binding domain is required for FKBP12-rapamycin-associated protein kinase activity and G1 progression. J. Biol. Chem. 274, 4266-4272 (1999).
41. Shor, B. et al. A new pharmacologic action of CCI-779 involves FKBP12-independent inhibition ofmTOR kinase activity and profound repression of global protein synthesis. Cancer Res. 68, 2934-2943 (2008).
42. Rodr?́guez, A. et al. A conserved docking surface on calcineurin mediates interaction with substrates and immunosuppressants. Mol. Cell 33, 616-626 (2009).
43. Ohne, Y. et al. Isolation of hyperactivemutants ofmammalian target of rapamycin. J. Biol. Chem. 283, 31861-31870 (2008).
44. Reinke, A., Chen, J. C., Aronova, S. & Powers, T. Caffeine targets TOR complex I and provides evidence for a regulatory link between the FRB and kinase domains of Tor1p. J. Biol. Chem. 281, 31616-31626 (2006).
45. Urano, J. et al. Point mutations in TOR confer Rheb-independent growth in fission yeast and nutrient-independent mammalian TOR signaling in mammalian cells. Proc. Natl Acad. Sci. USA 104, 3514-3519 (2007).
46. Liu, Q. et al. Discovery of 9-(6-aminopyridin-3-yl)-1-(3- (trifluoromethyl) phenyl)benzo[h][1,6]naphthyridin-2(1H)-one (Torin2) as a potent, selective, and orally available mammalian target of rapamycin (mTOR) inhibitor for treatment of cancer. J. Med. Chem. 54, 1473-1480 (2011).
47. Apsel, B. et al. Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases. Nature Chem. Biol. 4, 691-699 (2008).
48. Knight, Z. A. et al. A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell 125, 733-747 (2006).
49. Otwinowski, Z. & Minor, W. Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276, 307-326 (1997).
50. Bricogne, G., Vonrhein, C., Flensburg, C., Schiltz, M. & Paciorek, W. Generation, representation and flow of phase information in structure determination: recent developments in and around SHARP 2.0. Acta Crystallogr. D 59, 2023-2030 (2003).
51. Collaborative Computational Project, Number 4. The CCP4 suite: programs for protein crystallography. Acta Crystallogr. D 50, 760-763 (1994).
52. Jones, T. A., Zou, J. Y., Cowan, S. W. & Kjeldgaard, M. Improved methods for building protein models in electron density maps and the location of errors in these models. Acta Crystallogr. A 47, 110-119 (1991).
53. Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D 66, 213-221 (2010).