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Cryo-EM structures of cancer-specific helical and kinase domain mutations of PI3K alpha

文献类型：期刊论文

作者Liu, Xiao2; Zhou, Qingtong2; Hart, Jonathan R.3; Xu, Yingna2; Yang, Su3; Yang, Dehua1,4,5; Vogt, Peter K.3; Wang, Ming-Wei2,5,6
刊名PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
出版日期2022-11-15
卷号119期号:46页码:11
关键词phosphoinositide 3-kinase (PI3K) mass spectrometry mutants
ISSN号0027-8424
DOI10.1073/pnas.2215621119
通讯作者Yang, Dehua(dhyang@simm.ac.cn) ; Vogt, Peter K.(pkvogt@scripps.edu) ; Wang, Ming-Wei(mwwang@simm.ac.cn)
英文摘要Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that perform multiple and important cellular functions. The protein investigated here belongs to class IA of the PI3Ks; it is a dimer consisting of a catalytic subunit, p110 alpha, and a regulatory subunit, p85 alpha, and is referred to as PI3K alpha. The catalytic subunit p110 alpha is frequently mutated in cancer. The mutations induce a gain of function and constitute a driving force in cancer development. About 80% of these mutations lead to single-amino-acid substitutions in one of three sites of p110 alpha: two in the helical domain of the protein (E542K and E545K) and one at the C-terminus of the kinase domain (H1047R). Here, we report the cryo-electron microscopy structures of these mutants in complex with the p110 alpha-specific inhibitor BYL-719. The H1047R mutant rotates its sidechain to a new position and weakens the k alpha 11 activation loop interaction, thereby reducing the inhibitory effect of p85 alpha on p110 alpha. E542K and E545K completely abolish the tight interaction between the helical domain of p110 alpha and the N-terminal SH2 domain of p85 alpha and lead to the disruption of all p85a binding and a dramatic increase in flexibility of the adaptor-binding domain (ABD) in p110 alpha. Yet, the dimerization of PI3K alpha is preserved through the ABD-p85 alpha interaction. The local and global structural features induced by these mutations provide molecular insights into the activation of PI3K alpha, deepen our understanding of the oncogenic mechanism of this important signaling molecule, and may facilitate the development of mutant-specific inhibitors.
WOS关键词PHOSPHOINOSITIDE 3-KINASES ; LIPID-BINDING ; PI3K PATHWAY ; ACTIVATION ; MECHANISM ; NVP-BYL719 ; P110-ALPHA ; FEATURES ; RECEPTOR ; FAMILY
资助项目National Natural Science Foundation of China[81872915] ; National Natural Science Foundation of China[82073904] ; National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[81973373] ; National Natural Science Foundation of China[21704064] ; National Science and Technology Major Project of China-Key New Drug Creation and Manufacturing Program[2018ZX09735-001] ; National Science and Technology Major Project of China-Key New Drug Creation and Manufacturing Program[2018ZX09711002-002-005] ; National Key Basic Research Program of China[2018YFA0507000] ; Hainan Provincial Major Science and Technology Project[ZDKJ2021028] ; Novo Nordisk-Chinese Academy of Sciences Research Fund[NNCAS-2017-1-CC] ; National Cancer Institute[R35 CA197582] ; National Cancer Institute[R50 CA243899] ; National Science and Technology Major Project of China-Innovation 2030 for Brain Science and Brain-Inspired Technology[2021ZD0203400]
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:000980665600013
出版者NATL ACAD SCIENCES
源URL[http://119.78.100.183/handle/2S10ELR8/306560]  
专题中国科学院上海药物研究所
通讯作者Yang, Dehua; Vogt, Peter K.; Wang, Ming-Wei
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
2.Fudan Univ, Sch Bas Med Sci, Dept Pharmacol, Shanghai 200032, Peoples R China
3.Scripps Res Inst, Dept Mol Med, La Jolla, CA 92037 USA
4.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China
5.Res Ctr Deepsea Bioresources, Sanya 572025, Peoples R China
6.Univ Tokyo, Sch Sci, Dept Chem, Tokyo 1130033, Japan
推荐引用方式
GB/T 7714		 Liu, Xiao,Zhou, Qingtong,Hart, Jonathan R.,et al. Cryo-EM structures of cancer-specific helical and kinase domain mutations of PI3K alpha[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2022,119(46):11.
APA Liu, Xiao.,Zhou, Qingtong.,Hart, Jonathan R..,Xu, Yingna.,Yang, Su.,...&Wang, Ming-Wei.(2022).Cryo-EM structures of cancer-specific helical and kinase domain mutations of PI3K alpha.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,119(46),11.
MLA Liu, Xiao,et al."Cryo-EM structures of cancer-specific helical and kinase domain mutations of PI3K alpha".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 119.46(2022):11.

入库方式： OAI收割

来源：上海药物研究所

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