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Structure. 2020 Feb 4. pii: S0969-2126(20)30010-1. doi: 10.1016/j.str.2020.01.010. [Epub ahead of print]

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

Author information

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

PMID:
32049032
DOI:
10.1016/j.str.2020.01.010

Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

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