Structures of the human cholecystokinin receptors in complex with agonists and antagonists

Abstract

Cholecystokinin 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.

Precision peptide theranostics: developing N- to C-terminus optimized theranostics targeting cholecystokinin-2 receptor

“…Recently, cryo-electron microscopy confirmed that the 17 amino acid long hormone gastrin-17 indeed forms a β-hairpin structure upon binding to CCK 2 R with the five C -terminal residues inserting deeply into the binding pocket of CCK 2 R 42 . Furthermore, the N -terminal section of gastrin-17 also orientates into a shallow binding cavity of CCK 2 R 42 .…”

“…Interestingly, Peggion and coworkers also demonstrated that Glu-residues at positions 1 and 2 of des-Trp 1 ,Nle 2 -MG form hydrogen bonds to Glu residues 5 and 6, to form the anticipated α-helical structure of N-terminus [40]. Recently, cryo-electron microscopy confirmed that the 17 amino acid long hormone gastrin-17 indeed forms a β-hairpin structure upon binding to CCK2R with the five C-terminal residues inserting deeply into the binding pocket of CCK 2 R [42]. Furthermore, the N-terminal section of gastrin-17 also orientates into a shallow binding cavity of CCK 2 R [42].…”

Estimation levels of cholecystokinin, gastrin and secretin in patients with type 2 diabetes mellitus

“…This is done by utilizing the molecular basis underlying the receptors' selectivity. In order to perform its essential activities, such as controlling insulin secretion and sustaining beta-cell functioning [10]. The CCK hormone must connect to certain ).…”