Ligand recognition and G-protein coupling selectivity of cholecystokinin A receptor

Nat Chem Biol. 2021 Dec;17(12):1238-1244. doi: 10.1038/s41589-021-00841-3.

Qiufeng Liu ^# ¹, Dehua Yang ^# ¹ ² ³, Youwen Zhuang ^# ¹, Tristan I Croll ⁴, Xiaoqing Cai ³, Antao Dai ³, Xinheng He ¹ ², Jia Duan ¹ ², Wanchao Yin ¹, Chenyu Ye ⁵, Fulai Zhou ¹, Beili Wu ¹ ² ⁶ ⁷, Qiang Zhao ² ⁷ ⁸, H Eric Xu ⁹ ¹⁰ ¹¹, Ming-Wei Wang ¹² ¹³ ¹⁴ ¹⁵ ¹⁶ ¹⁷, Yi Jiang ¹⁸ ¹⁹

Affiliations

1 The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
2 University of Chinese Academy of Sciences, Beijing, China.
3 The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
4 Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
5 School of Pharmacy, Fudan University, Shanghai, China.
6 School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
7 CAS Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing, China.
8 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
9 The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
10 University of Chinese Academy of Sciences, Beijing, China. [email protected].
11 School of Life Science and Technology, ShanghaiTech University, Shanghai, China. [email protected].
12 The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
13 University of Chinese Academy of Sciences, Beijing, China. [email protected].
14 The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
15 School of Pharmacy, Fudan University, Shanghai, China. [email protected].
16 School of Life Science and Technology, ShanghaiTech University, Shanghai, China. [email protected].
17 School of Basic Medical Sciences, Fudan University, Shanghai, China. [email protected].
18 The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
19 University of Chinese Academy of Sciences, Beijing, China. [email protected].
# Contributed equally.

PMID: 34556862 DOI: 10.1038/s41589-021-00841-3

Abstract

Cholecystokinin A receptor (CCK_AR) 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 CCK_AR is its ability to interact with a sulfated ligand and to couple with divergent G-protein subtypes, including G_s, G_i and G_q. However, the basis for G-protein coupling promiscuity and ligand recognition by CCK_AR remains unknown. Here, we present three cryo-electron microscopy structures of sulfated CCK-8-activated CCK_AR in complex with G_s, G_i and G_q heterotrimers, respectively. CCK_AR 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 CCK_AR and uncover the mechanism of receptor recognition by sulfated CCK-8.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-11074

CE-326597

CCKAR Small Molecule Agonist

Cholecystokinin Receptor

Metabolic Disease

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