Investigating the Structure and Dynamics of the PIK3CA Wild-Type and H1047R Oncogenic Mutant

PLoS Computational Biology

Volumn 10, Issue 10, 2014, Pages

  Gkeka, Paraskevi ^a   Evangelidis, Thomas ^a   Pavlaki, Maria ^b   Lazani, Vasiliki ^c   Christoforidis, Savvas ^c,d   Agianian, Bogos ^b   Cournia, Zoe ^a  

^a Academy of Athens Biomedical Research Foundation   (Greece)

^b DEMOCRITUS UNIVERSITY OF THRACE   (Greece)

^c Department of Biomedical Research Institute of Molecular Biology and Biotechnology Foundation for Research and Technology (IMBB BR FORTH)   (Greece)

^d UNIVERSITY OF IOANNINA   (Greece)

Author keywords

[No Author keywords available]

Indexed keywords

CELL PROLIFERATION; CELL SIGNALING; DISEASES; ONCOGENIC VIRUSES; PROTEINS; SURFACE PLASMON RESONANCE;

CATALYTIC SUBUNITS; DYNAMICS SIMULATION; HUMAN CANCER; MUTANT PROTEINS; ONCOGENIC MUTANTS; PHOSPHATIDYLINOSITOL 3-KINASE; STRUCTURE AND DYNAMICS; SURFACE-PLASMON RESONANCE; WILD TYPES; WILD-TYPE PROTEINS;

MOLECULAR DYNAMICS;

ALANINE; ARGININE; ASPARTIC ACID; GLYCINE; HISTIDINE; ISOLEUCINE; LEUCINE; LIPID; LIPOSOME; METHIONINE; PHENYLALANINE; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE ALPHA; TRYPTOPHAN; UNCLASSIFIED DRUG; PIK3CA PROTEIN, HUMAN; PROTEIN BINDING; TUMOR PROTEIN;

AMINO ACID SUBSTITUTION; ARTICLE; BINDING SITE; CARBOXY TERMINAL SEQUENCE; COMPARATIVE STUDY; CONTROLLED STUDY; ENZYME ACTIVITY; ENZYME SPECIFICITY; GENE; GENE MUTATION; GENE STRUCTURE; HUMAN; HUMAN CELL; HYDROGEN BOND; LIPOSOME MEMBRANE; MOLECULAR DYNAMICS; MOLECULAR MODEL; PIK3CA GENE; PROTEIN BINDING; PROTEIN LOCALIZATION; PROTEIN PROTEIN INTERACTION; PROTEIN STRUCTURE; SURFACE PLASMON RESONANCE; WILD TYPE; BIOLOGICAL MODEL; CHEMISTRY; CLUSTER ANALYSIS; GENETICS; METABOLISM; MUTATION; NEOPLASM;

CLUSTER ANALYSIS; HUMANS; MODELS, BIOLOGICAL; MOLECULAR DYNAMICS SIMULATION; MUTATION; NEOPLASM PROTEINS; NEOPLASMS; PHOSPHATIDYLINOSITOL 3-KINASES; PROTEIN BINDING; SURFACE PLASMON RESONANCE;

EID: 84908347335     PISSN: 1553734X     EISSN: 15537358     Source Type: Journal    
DOI: 10.1371/journal.pcbi.1003895     Document Type: Article

References (36)

1. Courtney KD, Corcoran RB, Engelman JA, (2010) The PI3K pathway as drug target in human cancer. J Clin Oncol 28: 1075–1083.
2. Samuels Y, Diaz LA, JrSchmidt-Kittler O, Cummins JM, Delong L, et al. (2005) Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 7: 561–573.
3. Yuan TL, Cantley LC, (2008) PI3K pathway alterations in cancer: variations on a theme. Oncogene 27: 5497–5510.
4. Backer JM, (2010) The regulation of class IA PI 3-kinases by inter-subunit interactions. Curr Top Microbiol Immunol 346: 87–114.
5. Gymnopoulos M, Elsliger MA, Vogt PK, (2007) Rare cancer-specific mutations in PIK3CA show gain of function. Proc Natl Acad Sci U S A 104: 5569–5574.
6. Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR, et al. (2008) Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 14: 1351–1356.
7. Meyer DS, Brinkhaus H, Muller U, Muller M, Cardiff RD, et al. (2011) Luminal expression of PIK3CA mutant H1047R in the mammary gland induces heterogeneous tumors. Cancer Res 71: 4344–4351.
8. Hon W-C, Berndt A, Williams R, (2012) Regulation of lipid binding underlies the activation mechanism of class IA PI3-kinases. Oncogene 31: 3655–3666.
9. Zhao L, Vogt PK, (2008) Helical domain and kinase domain mutations in p110alpha of phosphatidylinositol 3-kinase induce gain of function by different mechanisms. Proc Natl Acad Sci U S A 105: 2652–2657.
10. Carson JD, Van Aller G, Lehr R, Sinnamon RH, Kirkpatrick RB, et al. (2008) Effects of oncogenic p110alpha subunit mutations on the lipid kinase activity of phosphoinositide 3-kinase. Biochem J 409: 519–524.
11. Huang CH, Mandelker D, Schmidt-Kittler O, Samuels Y, Velculescu VE, et al. (2007) The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations. Science 318: 1744–1748.
12. Mandelker D, Gabelli SB, Schmidt-Kittler O, Zhu J, Cheong I, et al. (2009) A frequent kinase domain mutation that changes the interaction between PI3Kalpha and the membrane. Proc Natl Acad Sci U S A 106: 16996–17001.
13. Burke JE, Perisic O, Masson GR, Vadas O, Williams RL, (2012) Oncogenic mutations mimic and enhance dynamic events in the natural activation of phosphoinositide 3-kinase p110alpha (PIK3CA). Proc Natl Acad Sci U S A 109: 15259–15264.
14. Vadas O, Burke JE, Zhang X, Berndt A, Williams RL, (2011) Structural basis for activation and inhibition of class I phosphoinositide 3-kinases. Sci Signal 4: re2.
15. Miller S, Tavshanjian B, Oleksy A, Perisic O, Houseman BT, et al. (2010) Shaping development of autophagy inhibitors with the structure of the lipid kinase Vps34. Science 327: 1638–1642.
16. Zhang X, Vadas O, Perisic O, Anderson KE, Clark J, et al. (2011) Structure of lipid kinase p110beta/p85beta elucidates an unusual SH2-domain-mediated inhibitory mechanism. Mol Cell 41: 567–578.
17. Laurie AT, Jackson RM, (2005) Q-SiteFinder: an energy-based method for the prediction of protein-ligand binding sites. Bioinformatics 21: 1908–1916.
18. Williams R, Berndt A, Miller S, Hon WC, Zhang X, (2009) Form and flexibility in phosphoinositide 3-kinases. Biochem Soc Trans 37: 615–626.
19. Mankoo PK, Sukumar S, Karchin R, (2009) PIK3CA somatic mutations in breast cancer: Mechanistic insights from Langevin dynamics simulations. Proteins 75: 499–508.
20. Williams JC, Wierenga RK, Saraste M, (1998) Insights into Src kinase functions: structural comparisons. Trends Biochem Sci 23: 179–184.
21. Pirola L, Zvelebil MJ, Bulgarelli-Leva G, Van Obberghen E, Waterfield MD, et al. (2001) Activation loop sequences confer substrate specificity to phosphoinositide 3-kinase alpha (PI3Kalpha). Functions of lipid kinase-deficient PI3Kalpha in signaling. J Biol Chem 276: 21544–21554.
22. Lovera S, Sutto L, Boubeva R, Scapozza L, Dolker N, et al. (2012) The different flexibility of c-Src and c-Abl kinases regulates the accessibility of a druggable inactive conformation. J Am Chem Soc 134: 2496–2499.
23. Walker EH, Pacold ME, Perisic O, Stephens L, Hawkins PT, et al. (2000) Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol Cell 6: 909–919.
24. Knight ZA, Gonzalez B, Feldman ME, Zunder ER, Goldenberg DD, et al. (2006) A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell 125: 733–747.
25. Phillips JC, Braun R, Wang W, Gumbart J, Tajkhorshid E, et al. (2005) Scalable molecular dynamics with NAMD. J Comput Chem 26: 1781–1802.
26. Brooks BR, Brooks CL, 3rdMackerell AD, JrNilsson L, Petrella RJ, et al. (2009) CHARMM: the biomolecular simulation program. J Comput Chem 30: 1545–1614.
27. MacKerell AD, Bashford D, Bellott M, Dunbrack RL, Evanseck JD, et al. (1998) All-atom empirical potential for molecular modeling and dynamics studies of proteins. J Phys Chem B 102: 3586–3616.
28. Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML, (1983) Comparison of Simple Potential Functions for Simulating Liquid Water. J Chem Phys 79: 926–935.
29. Rog T, Murzyn K, Hinsen K, Kneller GR, (2003) nMoldyn: a program package for a neutron scattering oriented analysis of molecular dynamics simulations. J Comput Chem 24: 657–667.
30. Hinsen K, (2000) The molecular modeling toolkit: A new approach to molecular simulations. J Comput Chem 21: 79–85.
31. Hess B, Carsten K, David vdS, Erik L, (2008) GROMACS 4: Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation. Journal of Chemical Theory and Computation 4: 435–447.
32. Dolinsky TJ, Czodrowski P, Li H, Nielsen JE, Jensen JH, et al. (2007) PDB2PQR: Expanding and upgrading automated preparation of biomolecular structures for molecular simulations. Nucleic Acids Res 35: W522–525.
33. Baker NA, Sept D, Joseph S, Holst MJ, McCammon JA, (2001) Electrostatics of nanosystems: application to microtubules and the ribosome. Proc Natl Acad Sci U S A 98: 10037–10041.
34. Humphrey W, Dalke A, Schulten K, (1996) VMD: visual molecular dynamics. J Mol Graph 14: 33–38.
35. Hub JS, de Groot BL, (2009) Detection of functional modes in protein dynamics. PLoS Comput Biol 5: e1000480.
36. Folch J, Lees M, Sloane Stanley GH, (1957) A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem 226: 497–509.