Open AccessCryo-EM structures of PI3Kα reveal conformational changes during inhibition and activation
Author(s) -
Xiao Liu,
Yang Su,
Jonathan R. Hart,
Yingna Xu,
Xinyu Zou,
Huibing Zhang,
Qingtong Zhou,
Tian Xia,
Yan Zhang,
Dehua Yang,
Mingwei Wang,
Peter K. Vogt
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2109327118
Subject(s) - phosphopeptide , pi3k/akt/mtor pathway , chemistry , kinase , phosphoinositide 3 kinase , p110α , biophysics , protein kinase domain , crystallography , biochemistry , biology , signal transduction , mutant , gene
Significance Phosphoinositide 3-kinases (PI3Ks) are of critical importance in cell signaling and can function as drivers of disease. Information on the PI3K structure is essential for an understanding of the function of these proteins and for the identification of specific and effective small-molecule inhibitors. Here we present a single-particle cryo-electron microscopy (cryo-EM) analysis of PI3Kα, the dimer consisting of the p110α catalytic subunit bound to the p85α regulatory subunit. We investigated three conformational states of PI3Kα: the unbound dimer, the dimer bound to the isoform-specific inhibitor BYL-719, and the dimer associated with an activating phosphopeptide. Each of these conformations reveals specific structural features that provide insights into conformation-associated functions.