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TitleCryo-EM structures reveal two allosteric inhibition modes of PI3Kα involving a re-shaping of the activation loop.
Journal, issue, pagesStructure, Year 2024
Publish dateMar 26, 2024
AuthorsXiuliang Huang / Kailiang Wang / Jing Han / Xiumei Chen / Zhenglin Wang / Tianlun Wu / Bo Yu / Feng Zhao / Xinjuan Wang / Huijuan Li / Zhi Xie / Xiaotian Zhu / Wenge Zhong / Xiaoming Ren /
PubMed AbstractPI3Kα 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 ...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.
External linksStructure / PubMed:38582077
MethodsEM (single particle)
Resolution2.7 - 3.0 Å
Structure data

37362

8w9a

EMDB-37362, PDB-8w9a:
CryoEM structure of human PI3K-alpha (P85/P110-H1047R) with QR-7909 binding at an allosteric site
Method: EM (single particle) / Resolution: 2.7 Å

37363

8w9b

EMDB-37363, PDB-8w9b:
CryoEM structure of human PI3K-alpha (P85/P110-H1047R) with QR-8557 binding at an allosteric site
Method: EM (single particle) / Resolution: 3.0 Å

Chemicals


ChemComp, No image

ChemComp-UEX:
Unknown entry

ChemComp-HOH:
WATER / Water


ChemComp, No image

ChemComp-UJ3:
Unknown entry

Source
  • homo sapiens (human)
KeywordsONCOPROTEIN / PI3K-alpha / lipid kinase / allosteric inhibition

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