Journal Article

Structures of the human cholecystokinin receptors bound to agonists and antagonists

Zhang, Hui, Tan, Qiuxiang, He, Chenglin, Han, Shuo, Zhang, Xuefeng, Yang, Zhenlin, Wang, Mu, Chu, Xiaojing, Xu, H. Eric, Feng, Wenbo, Wang, Jia, Jiang, Yi, Zhu, Ya, Zhao, Suwen, Yang, Dehua, Wang, Ming-Wei, Sensfuss, Ulrich, Zhao, Qiang, Dai, Antao, Wu, Beili, Zhou, Qingtong, Reedtz-Runge, Steffen

2021

Overview

Cholecystokinin receptors, CCK A R and CCK B R, are important neurointestinal peptide hormone receptors and play a vital role in food intake and appetite regulation. Here, we report three crystal structures of the human CCK A R in complex with different ligands, including one peptide agonist and two small-molecule antagonists, as well as two cryo-electron microscopy structures of CCK B R–gastrin in complex with G i2 and G q , 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. Structures of human cholecystokinin receptors in complex with various ligands or G-proteins reveal how different ligand types are recognized and the basis of peptide selectivity in this receptor family, and suggest a stepwise activation mechanism.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/535/1266 / 631/80/86 / 631/92/611 / 631/92/612/194 / Agonists / Amino Acid Sequence / Appetite / Biochemical Engineering / Biochemistry / Bioorganic Chemistry / Cell Biology / Chemistry / Chemistry and Materials Science / Chemistry/Food Science / Cholecystokinin / Cholecystokinin receptors / Coordination compounds / Cryoelectron Microscopy / Crystal structure / Crystallization / Devazepide - chemistry / Electron microscopy / Food intake / Gastrin / Humans / Indoleacetic Acids - chemistry / Ligands / Models, Molecular / Pattern recognition / Peptides / Protein Binding / Protein Conformation / Receptor mechanisms / Receptors / Receptors, Cholecystokinin - chemistry / Receptors, Cholecystokinin - genetics / Selectivity / Structure-Activity Relationship / Thiazoles - chemistry