Ligand recognition and G-protein coupling selectivity of cholecystokinin A receptor.
Authors
Liu, Qiufeng
Zhuang, Youwen
Cai, Xiaoqing
Dai, Antao
Duan, Jia
Ye, Chenyu
Wang, Ming-Wei
Publication Date
2021-12Journal Title
Nat Chem Biol
ISSN
1552-4450
Publisher
Springer Science and Business Media LLC
Volume
17
Issue
12
Pages
1238-1244
Language
en
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Liu, Q., Yang, D., Zhuang, Y., Croll, T., Cai, X., Dai, A., He, X., et al. (2021). Ligand recognition and G-protein coupling selectivity of cholecystokinin A receptor.. Nat Chem Biol, 17 (12), 1238-1244. https://doi.org/10.1038/s41589-021-00841-3
Abstract
Cholecystokinin A receptor (CCKAR) belongs to family A G-protein-coupled receptors and regulates nutrient homeostasis upon stimulation by cholecystokinin (CCK). It is an attractive drug target for gastrointestinal and metabolic diseases. One distinguishing feature of CCKAR is its ability to interact with a sulfated ligand and to couple with divergent G-protein subtypes, including Gs, Gi and Gq. However, the basis for G-protein coupling promiscuity and ligand recognition by CCKAR remains unknown. Here, we present three cryo-electron microscopy structures of sulfated CCK-8-activated CCKAR in complex with Gs, Gi and Gq heterotrimers, respectively. CCKAR presents a similar conformation in the three structures, whereas conformational differences in the 'wavy hook' of the Gα subunits and ICL3 of the receptor serve as determinants in G-protein coupling selectivity. Our findings provide a framework for understanding G-protein coupling promiscuity by CCKAR and uncover the mechanism of receptor recognition by sulfated CCK-8.
Keywords
Article, /631/535, /631/92/612/194, /631/154/436, /631/80/86, article
Sponsorship
Wellcome Trust (209407/Z/17/Z)
Identifiers
s41589-021-00841-3, 841
External DOI: https://doi.org/10.1038/s41589-021-00841-3
This record's URL: https://www.repository.cam.ac.uk/handle/1810/330925
Rights
Licence:
http://creativecommons.org/licenses/by/4.0/
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