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Cryo-EM structures of PI3K alpha reveal conformational changes during inhibition and activation

文献类型：期刊论文

作者Liu, Xiao1; Yang, Su2; Hart, Jonathan R.2; Xu, Yingna1; Zou, Xinyu3; Zhang, Huibing4,5; Zhou, Qingtong6; Xia, Tian3; Zhang, Yan4,5; Yang, Dehua7,8,9
刊名PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
出版日期2021-11-09
卷号118期号:45页码:9
ISSN号0027-8424
关键词phosphoinositide 3-kinase (PI3K) activation inhibition activity-dependent conformational changes
DOI10.1073/pnas.2109327118
通讯作者Yang, Dehua(dhyang@simm.ac.cn) ; Wang, Ming-Wei(mwwang@simm.ac.cn) ; Vogt, Peter K.(pkvogt@scripps.edu)
英文摘要Phosphoinositide 3-kinases (PI3Ks) are lipid kinases essential for growth and metabolism. Their aberrant activation is associated with many types of cancers. Here we used single-particle cryoelectron microscopy (cryo-EM) to determine three distinct conformations of full-length PI3K alpha (p110 alpha-p85 alpha): the unliganded heterodimer PI3K alpha, PI3K alpha bound to the p110 alpha-specific inhibitor BYL-719, and PI3K alpha exposed to an activating phosphopeptide. The cryo-EM structures of unbound and of BYL-719-bound PI3K alpha are in general accord with published crystal structures. Local deviations are presented and discussed. BYL-719 stabilizes the structure of PI3K alpha, but three regions of low-resolution extra density remain and are provisionally assigned to the cSH2, BH, and SH3 domains of p85. One of the extra density regions is in contact with the kinase domain blocking access to the catalytic site. This conformational change indicates that the effects of BYL-719 on PI3K alpha activity extend beyond competition with adenosine triphosphate (ATP). In unliganded PI3K alpha, the DFG motif occurs in the "in" and "out" positions. In BYL-719-bound PI3K alpha, only the DFG-in position, corresponding to the active conformation of the kinase, was observed. The phosphopeptide-bound structure of PI3K alpha is composed of a stable core resolved at 3.8 angstrom. It contains all p110 alpha domains except the adaptor-binding domain (ABD). The p85 alpha domains, linked to the core through the ABD, are no longer resolved, implying that the phosphopeptide activates PI3K alpha by fully releasing the niSH2 domain from binding to p110 alpha. The structures presented here show the basal form of the full-length PI3K alpha dimer and document conformational changes related to the activated and inhibited states.
WOS关键词TERMINAL SH2 DOMAIN ; PHOSPHOINOSITIDE 3-KINASES ; P85-ALPHA SUBUNIT ; HUMAN CANCER ; PIK3CA GENE ; MUTATIONS ; PI3K ; BINDING ; VISUALIZATION ; NVP-BYL719
资助项目National Natural Science Foundation of China[81872915] ; National Natural Science Foundation of China[82073904] ; National Natural Science Foundation of China[81922071] ; National Natural Science Foundation of China[81773792] ; National Natural Science Foundation of China[81973373] ; National Natural Science Foundation of China[21704064] ; National Science & Technology Major Project of China-Key New Drug Creation and Manufacturing Program[2018ZX09735-001] ; National Science & Technology Major Project of China-Key New Drug Creation and Manufacturing Program[2018ZX09711002-002-005] ; National Key Basic Research Program of China[2018YFA0507000] ; National Key Basic Research Program of China[2019YFA0508800] ; Novo Nordisk-CAS Research Fund[NNCAS-2017-1-CC] ; National Cancer Institute[R35 CA197582] ; National Cancer Institute[R50 CA243899]
WOS研究方向Science & Technology - Other Topics
语种英语
出版者NATL ACAD SCIENCES
WOS记录号WOS:000720928400004
源URL[http://119.78.100.183/handle/2S10ELR8/299015]  
专题中国科学院上海药物研究所
通讯作者Yang, Dehua; Wang, Ming-Wei; Vogt, Peter K.
作者单位1.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China
2.Scripps Res Inst, Dept Mol Med, La Jolla, CA 92037 USA
3.Huazhong Univ Sci & Technol, Sch Artificial Intelligence & Automat, Wuhan 430074, Peoples R China
4.Zhejiang Univ, Sir Run Run Shaw Hosp, Dept Biophys, Sch Med, Hangzhou 310058, Peoples R China
5.Zhejiang Univ, Sir Run Run Shaw Hosp, Dept Pathol, Sch Med, Hangzhou 310058, Peoples R China
6.Fudan Univ, Sch Basic Med Sci, Dept Pharmacol, Shanghai 200032, Peoples R China
7.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
8.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
9.Res Ctr Deep Sea Bioresources, Sanya 572025, Hainan, Peoples R China
10.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
推荐引用方式
GB/T 7714		 Liu, Xiao,Yang, Su,Hart, Jonathan R.,et al. Cryo-EM structures of PI3K alpha reveal conformational changes during inhibition and activation[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2021,118(45):9.
APA Liu, Xiao.,Yang, Su.,Hart, Jonathan R..,Xu, Yingna.,Zou, Xinyu.,...&Vogt, Peter K..(2021).Cryo-EM structures of PI3K alpha reveal conformational changes during inhibition and activation.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,118(45),9.
MLA Liu, Xiao,et al."Cryo-EM structures of PI3K alpha reveal conformational changes during inhibition and activation".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 118.45(2021):9.

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来源：上海药物研究所

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