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

Mayukh Chakrabarti; Sandra B Gabelli; L Mario Amzel

doi:10.1016/j.str.2020.01.010

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

Structure. 2020 Apr 7;28(4):465-474.e5. doi: 10.1016/j.str.2020.01.010. Epub 2020 Feb 10.

Authors

Mayukh Chakrabarti¹, Sandra B Gabelli², L Mario Amzel³

Affiliations

¹ Structural Enzymology and Thermodynamics Group, Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, 725 North Wolfe Street, 606 WBSB 608, Baltimore, MD 21205, USA.
² Structural Enzymology and Thermodynamics Group, Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, 725 North Wolfe Street, 606 WBSB 608, Baltimore, MD 21205, USA; Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross Building 844, Baltimore, MD 21205, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
³ Structural Enzymology and Thermodynamics Group, Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, 725 North Wolfe Street, 606 WBSB 608, Baltimore, MD 21205, USA. Electronic address: mamzel@jhmi.edu.

Abstract

Class I phosphoinositide-3-kinases (PI3Ks) phosphorylate PIP₂ at its 3' inositol position to generate PIP₃, 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.

Keywords: catalytic mechanism; dynamic allostery; enzyme activation; molecular dynamics; phosphoinositide (3,4,5)-trisphosphate; phosphoinositide (4,5)-bisphosphate; phosphoinositide kinase; population increase; signaling pathway.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Allosteric Regulation
Catalytic Domain*
Molecular Dynamics Simulation*
Phosphatidylinositol 3-Kinases / chemistry*
Phosphatidylinositol 3-Kinases / metabolism
Phosphatidylinositol 4,5-Diphosphate / chemistry
Phosphatidylinositol 4,5-Diphosphate / metabolism
Protein Binding
Tyrosine / chemistry
Tyrosine / metabolism
src Homology Domains

Substances

Phosphatidylinositol 4,5-Diphosphate
Tyrosine

Abstract

Publication types

MeSH terms

Substances

Grants and funding