Structures of the human cholecystokinin receptors bound to agonists and antagonists

被引：37

作者：

Zhang, Xuefeng ^{[1
,2
,3
]}

He, Chenglin ^{[4
]}

Wang, Mu ^{[1
,2
,3
,5
]}

Zhou, Qingtong ^{[6
,7
]}

Yang, Dehua ^{[1
,2
,3
,8
]}

Zhu, Ya ^{[1
,2
]}

Feng, Wenbo ^{[4
]}

Zhang, Hui ^{[1
,2
,3
]}

Dai, Antao ^{[8
]}

Chu, Xiaojing ^{[1
,2
]}

Wang, Jia ^{[8
]}

Yang, Zhenlin ^{[1
,2
]}

Jiang, Yi ^{[1
,2
]}

Sensfuss, Ulrich ^{[9
]}

Tan, Qiuxiang ^{[1
,2
]}

Han, Shuo ^{[1
,2
]}

Reedtz-Runge, Steffen ^{[9
]}

Xu, H. Eric ^{[1
,2
,3
]}

Zhao, Suwen ^{[5
,6
]}

Wang, Ming-Wei ^{[1
,2
,3
,4
,5
,7
,8
]}

Wu, Beili ^{[1
,2
,3
,5
,10
]}

Zhao, Qiang ^{[1
,2
,3
,11
,12
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China

[2] Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai, Peoples R China

[3] Univ Chinese Acad Sci, Beijing, Peoples R China

[4] Fudan Univ, Sch Pharm, Shanghai, Peoples R China

[5] ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China

[6] ShanghaiTech Univ, iHuman Inst, Shanghai, Peoples R China

[7] Fudan Univ, Sch Basic Med Sci, Dept Pharmacol, Shanghai, Peoples R China

[8] Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai, Peoples R China

[9] Novo Nordisk AS, Malov, Denmark

[10] Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou, Peoples R China

[11] Chinese Aacademy Sci, Inst Drug Discovery, Zhongshan Inst Drug Discovery, Guangzhou, Guangdong, Peoples R China

[12] Chinese Aacademy Sci, Inst Dev, Zhongshan Inst Drug Discovery, Guangzhou, Guangdong, Peoples R China

来源：

NATURE CHEMICAL BIOLOGY | 2021年 / 17卷 / 12期

基金：

美国国家科学基金会;

关键词：

SUBTYPE SELECTIVITY; BIOLOGICAL-ACTIVITY; FORCE-FIELD; GASTRIN; CCK; BINDING; POTENT; MECHANISM; AFFINITY; GROMACS;

D O I：

10.1038/s41589-021-00866-8

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Cholecystokinin receptors, CCKAR and CCKBR, are important neurointestinal peptide hormone receptors and play a vital role in food intake and appetite regulation. Here, we report three crystal structures of the human CCKAR in complex with different ligands, including one peptide agonist and two small-molecule antagonists, as well as two cryo-electron microscopy structures of CCKBR-gastrin in complex with G(i2) and G(q), respectively. These structures reveal the recognition pattern of different ligand types and the molecular basis of peptide selectivity in the cholecystokinin receptor family. By comparing receptor structures in different conformational states, a stepwise activation process of cholecystokinin receptors is proposed. Combined with pharmacological data, our results provide atomic details for differential ligand recognition and receptor activation mechanisms. These insights will facilitate the discovery of potential therapeutics targeting cholecystokinin receptors.

引用

页码：1230 / 1237

页数：8

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