Abstract
SummaryCholecystokinin receptors, CCKAR and CCKBR, are important neuro-intestinal 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 Gi2 and Gq, 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.
Publisher
Cold Spring Harbor Laboratory
Reference51 articles.
1. Phylogeny of the Cholecystokinin/Gastrin Family
2. The Biology of Cholecystokinin and Gastrin Peptides
3. Cloning and sequence analysis of a cDNA encoding rat preprocholecystokinin.
4. Cholecystokinin-From Local Gut Hormone to Ubiquitous Messenger;Front Endocrinol (Lausanne),2017
5. Gastric Peptides-Gastrin and Somatostatin;Comprehensive Physiology,2020