Structural and mechanistic insights provided by single particle cryo-EM analysis of phosphoinositide 3-kinase (PI3Kα)

Peter K Vogt; Jonathan R Hart; Su Yang; Qingtong Zhou; Dehua Yang; Ming-Wei Wang

doi:10.1016/j.bbcan.2023.188947

Structural and mechanistic insights provided by single particle cryo-EM analysis of phosphoinositide 3-kinase (PI3Kα)

Biochim Biophys Acta Rev Cancer. 2023 Sep;1878(5):188947. doi: 10.1016/j.bbcan.2023.188947. Epub 2023 Jun 30.

Authors

Peter K Vogt¹, Jonathan R Hart², Su Yang², Qingtong Zhou³, Dehua Yang⁴, Ming-Wei Wang⁵

Affiliations

¹ Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, United States of America. Electronic address: pkvogt@scripps.edu.
² Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, United States of America.
³ Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
⁴ The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁵ Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Research Center for Deepsea Bioresources, Sanya 572025, China; Department of Chemistry, School of Science, The University of Tokyo, Tokyo 113-0033, Japan.

PMID: 37394020
PMCID: PMC10530483 (available on 2024-09-01)
DOI: 10.1016/j.bbcan.2023.188947

Abstract

Recent cryo-electron microscopic (cryo-EM) investigations have succeeded in the analysis of various structural conformations and functional states of PI3Kα, a dimer consisting of the catalytic subunit p110α and the regulatory subunit p85α of class IA of phosphoinositide 3-kinase. High resolution structures have been obtained of the unliganded and of BYL-719-bound PI3Kα. The latter provides information on excessively flexible domains of p85α that are then further analyzed with nanobodies and CXMS (chemical cross-linking, digestion and mass spectrometry). Analysis of p110α helical and kinase domain mutations reveals mutant-specific features that can be linked to the gain of function in enzymatic and signaling activities.

Keywords: BYL-719; CXMS; Mutants; Nanobody; Phosphoinositide 3-kinase.

Publication types

Review
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Catalytic Domain / genetics
Cryoelectron Microscopy
Humans
Mutation
Phosphatidylinositol 3-Kinase*
Phosphatidylinositol 3-Kinases* / metabolism

Substances

Phosphatidylinositol 3-Kinase
Phosphatidylinositol 3-Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding