Structural basis for ligand recognition and G protein-coupling promiscuity of the cholecystokinin A receptor
Year: 2021
Type: preprint
Abstract: Cholecystokinin A receptor (CCK A R) belongs to family A G protein-coupled receptors (GPCRs) 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 A R is its ability to interact with 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 A R remain unknown. Here we present three cryo-electron microscopy (cryo-EM) structures of sulfated CCK-8 activated CCK A R in complex with G s , G i , and G q heterotrimers, respectively. In these three structures, CCK A R presents a similar conformation, whereas conformational differences in “wavy hook” of Gα subunits and ICL3 of the receptor serve as determinants in G protein coupling selectivity. These structures together with mutagenesis data provide the framework for understanding the G protein coupling promiscuity by CCK A R and uncover the mechanism of receptor recognition by sulfated CCK-8.
Institutions: Chinese Academy of Sciences, Shanghai Institute of Materia Medica, National Center for Drug Screening, University of Chinese Academy of Sciences, University of Cambridge, Fudan University, ShanghaiTech University, State Key Laboratory of Drug Research, Shanghai Medical College of Fudan University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: Wellcome Trust, National Natural Science Foundation of China, Chinese Academy of Sciences, Ministry of Science and Technology of the People's Republic of China, Science and Technology Commission of Shanghai Municipality, Novo Nordisk, National Science and Technology Major Project, National Key New Drug Creation and Manufacturing Program, Ministry of Science and Technology
Awards: G1046514286, G1625165766, G1688521625, G2488613150, G2606711600, G2988598348, G3244657092, G33758468, G339059223, G3586757494, G3762251729, G3800427001, G4093563242, G4363245776, Development of likelihood-based methods in structural biology, G4548387155, G4621043263, G4770872478, G619996574, G6387123747, G7057204618, G7101604325, G7816392389, G8631182429
OpenAlex ID: W3163023178