8W9B

CryoEM structure of human PI3K-alpha (P85/P110-H1047R) with QR-8557 binding at an allosteric site

Summary for 8W9B

• Entry DOI: 10.2210/pdb8w9b/pdb
• EMDB information: 37363
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform, Phosphatidylinositol 3-kinase regulatory subunit alpha, 1-[(1S)-1-(5-fluoranyl-3-methyl-1-benzofuran-2-yl)-2-methyl-propyl]-3-(1-oxidanylidene-2,3-dihydroisoindol-5-yl)urea (3 entities in total)
• Functional Keywords: pi3k-alpha, lipid kinase, allosteric inhibition, oncoprotein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 158293.14

Authors

Huang, X.,Ren, X.,Zhong, W. (deposition date: 2023-09-05, release date: 2024-04-17, Last modification date: 2024-07-24)

Primary citation

Huang, X.,Wang, K.,Han, J.,Chen, X.,Wang, Z.,Wu, T.,Yu, B.,Zhao, F.,Wang, X.,Li, H.,Xie, Z.,Zhu, X.,Zhong, W.,Ren, X.
Cryo-EM structures reveal two allosteric inhibition modes of PI3K alpha H1047R involving a re-shaping of the activation loop.
Structure, 32:907-917.e7, 2024

PubMed Abstract: PI3Kα is a lipid kinase that phosphorylates PIP2 and generates PIP3. The hyperactive PI3Kα mutation, H1047R, accounts for about 14% of breast cancer, making it a highly attractive target for drug discovery. Here, we report the cryo-EM structures of PI3Kα bound to two different allosteric inhibitors QR-7909 and QR-8557 at a global resolution of 2.7 Å and 3.0 Å, respectively. The structures reveal two distinct binding pockets on the opposite sides of the activation loop. Structural and MD simulation analyses show that the allosteric binding of QR-7909 and QR-8557 inhibit PI3Kα hyper-activity by reducing the fluctuation and mobility of the activation loop. Our work provides a strong rational basis for a further optimization and development of highly selective drug candidates to treat PI3Kα-driven cancers.

PubMed: 38582077
DOI: 10.1016/j.str.2024.03.007

Experimental method

ELECTRON MICROSCOPY (3 Å)