Allosteric Activation of PI3Kα Results in Dynamic Access to Catalytically Competent Conformations

Overview

Journal Structure

Publisher Cell Press

Specialties Biochemistry
Biotechnology
Cell Biology
Molecular Biology

Date 2020 Feb 13

PMID 32049032

Citations 10

Authors

Mayukh Chakrabarti

Sandra B Gabelli

L Mario Amzel

Affiliations

Soon will be listed here.

Abstract

Class I phosphoinositide-3-kinases (PI3Ks) phosphorylate PIP at its 3' inositol position to generate PIP, a second messenger that influences signaling cascades regulating cellular growth, survival, and proliferation. Previous studies have suggested that PI3Kα activation involves dislodging the p85α nSH2 domain from the p110α catalytic subunit by binding activated receptor tyrosine kinases. We carried out molecular dynamics simulations to determine, mechanistically and structurally, how PI3Kα conformations are influenced by physiological effectors and the nSH2 domain. We demonstrate that changes in protein dynamics mediated by allosteric regulation significantly increase the population of catalytically competent states without changing the enzyme ground-state structure. Furthermore, we demonstrate that modulation of active-site residue interactions with enzyme substrates can reciprocally influence nSH2 domain dynamics. Together, these results suggest that dynamic allostery plays a role in populating the catalytically competent conformation of PI3Kα, and provide a key platform for the design of novel chemotherapeutic PI3Kα inhibitors.

Citing Articles

Understanding the conformational dynamics of PI3Kα due to helical domain mutations: insights from Markov state model analysis.

Jani V, Sonavane U, Sawant S Mol Divers. 2025; .

PMID: 39982680 DOI: 10.1007/s11030-025-11138-1.

ATP-competitive inhibitors of PI3K enzymes demonstrate an isoform selective dual action by controlling membrane binding.

Gong G, Masson G, Lee W, Dickson J, Kendall J, Rathinaswamy M Biochem J. 2024; 481(23):1787-1802.

PMID: 39485310 PMC: 7617104. DOI: 10.1042/BCJ20240479.

Free energy landscape of the PI3Kα C-terminal activation.

Kotzampasi D, Papadourakis M, Burke J, Cournia Z Comput Struct Biotechnol J. 2024; 23:3118-3131.

PMID: 39229338 PMC: 11369385. DOI: 10.1016/j.csbj.2024.07.010.

Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia.

Varkaris A, Pazolli E, Gunaydin H, Wang Q, Pierce L, Boezio A Cancer Discov. 2023; 14(2):240-257.

PMID: 37916956 PMC: 10850943. DOI: 10.1158/2159-8290.CD-23-0944.

Oncogenic mutations of PIK3CA lead to increased membrane recruitment driven by reorientation of the ABD, p85 and C-terminus.

Jenkins M, Ranga-Prasad H, Parson M, Harris N, Rathinaswamy M, Burke J Nat Commun. 2023; 14(1):181.

PMID: 36635288 PMC: 9837058. DOI: 10.1038/s41467-023-35789-6.

References

Vanommeslaeghe K, Hatcher E, Acharya C, Kundu S, Zhong S, Shim J . CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields. J Comput Chem. 2009; 31(4):671-90. PMC: 2888302. DOI: 10.1002/jcc.21367. View

Campitelli P, Guo J, Zhou H, Ozkan S . Hinge-Shift Mechanism Modulates Allosteric Regulations in Human Pin1. J Phys Chem B. 2018; 122(21):5623-5629. PMC: 5980714. DOI: 10.1021/acs.jpcb.7b11971. View

Huang C, Mandelker D, Gabelli S, Amzel L . Insights into the oncogenic effects of PIK3CA mutations from the structure of p110alpha/p85alpha. Cell Cycle. 2008; 7(9):1151-6. PMC: 3260475. DOI: 10.4161/cc.7.9.5817. View

WALKER E, Perisic O, Ried C, Stephens L, Williams R . Structural insights into phosphoinositide 3-kinase catalysis and signalling. Nature. 1999; 402(6759):313-20. DOI: 10.1038/46319. View

Tse A, Verkhivker G . Molecular Dynamics Simulations and Structural Network Analysis of c-Abl and c-Src Kinase Core Proteins: Capturing Allosteric Mechanisms and Communication Pathways from Residue Centrality. J Chem Inf Model. 2015; 55(8):1645-62. DOI: 10.1021/acs.jcim.5b00240. View

Miller M, Schmidt-Kittler O, Bolduc D, Brower E, Chaves-Moreira D, Allaire M . Structural basis of nSH2 regulation and lipid binding in PI3Kα. Oncotarget. 2014; 5(14):5198-208. PMC: 4170646. DOI: 10.18632/oncotarget.2263. View

Cooper A, Dryden D . Allostery without conformational change. A plausible model. Eur Biophys J. 1984; 11(2):103-9. DOI: 10.1007/BF00276625. View

Leontiadou H, Galdadas I, Athanasiou C, Cournia Z . Insights into the mechanism of the PIK3CA E545K activating mutation using MD simulations. Sci Rep. 2018; 8(1):15544. PMC: 6195558. DOI: 10.1038/s41598-018-27044-6. View

Weinkam P, Pons J, Sali A . Structure-based model of allostery predicts coupling between distant sites. Proc Natl Acad Sci U S A. 2012; 109(13):4875-80. PMC: 3324024. DOI: 10.1073/pnas.1116274109. View

10.

Huang J, Rauscher S, Nawrocki G, Ran T, Feig M, de Groot B . CHARMM36m: an improved force field for folded and intrinsically disordered proteins. Nat Methods. 2016; 14(1):71-73. PMC: 5199616. DOI: 10.1038/nmeth.4067. View

11.

Fuentes E, Der C, Lee A . Ligand-dependent dynamics and intramolecular signaling in a PDZ domain. J Mol Biol. 2003; 335(4):1105-15. DOI: 10.1016/j.jmb.2003.11.010. View

12.

Malay A, Watanabe M, Heddle J, Tame J . Crystal structure of unliganded TRAP: implications for dynamic allostery. Biochem J. 2010; 434(3):427-34. PMC: 3048579. DOI: 10.1042/BJ20101813. View

13.

Wu H, Shekar S, Flinn R, El-Sibai M, Jaiswal B, Sen K . Regulation of Class IA PI 3-kinases: C2 domain-iSH2 domain contacts inhibit p85/p110alpha and are disrupted in oncogenic p85 mutants. Proc Natl Acad Sci U S A. 2009; 106(48):20258-63. PMC: 2787125. DOI: 10.1073/pnas.0902369106. View

14.

WALKER E, Pacold M, Perisic O, Stephens L, Hawkins P, Wymann M . Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol Cell. 2000; 6(4):909-19. DOI: 10.1016/s1097-2765(05)00089-4. View

15.

Maheshwari S, Miller M, OMeally R, Cole R, Amzel L, Gabelli S . Kinetic and structural analyses reveal residues in phosphoinositide 3-kinase α that are critical for catalysis and substrate recognition. J Biol Chem. 2017; 292(33):13541-13550. PMC: 5566514. DOI: 10.1074/jbc.M116.772426. View

16.

Humphrey W, Dalke A, Schulten K . VMD: visual molecular dynamics. J Mol Graph. 1996; 14(1):33-8, 27-8. DOI: 10.1016/0263-7855(96)00018-5. View

17.

Popovych N, Sun S, Ebright R, Kalodimos C . Dynamically driven protein allostery. Nat Struct Mol Biol. 2006; 13(9):831-8. PMC: 2757644. DOI: 10.1038/nsmb1132. View

18.

Tsai C, Sol A, Nussinov R . Allostery: absence of a change in shape does not imply that allostery is not at play. J Mol Biol. 2008; 378(1):1-11. PMC: 2684958. DOI: 10.1016/j.jmb.2008.02.034. View

19.

Vadas O, Burke J, Zhang X, Berndt A, Williams R . Structural basis for activation and inhibition of class I phosphoinositide 3-kinases. Sci Signal. 2011; 4(195):re2. DOI: 10.1126/scisignal.2002165. View

20.

Sali A, Blundell T . Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol. 1993; 234(3):779-815. DOI: 10.1006/jmbi.1993.1626. View