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

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

Posted 21 May 2021
bioRxiv DOI: 10.1101/2021.05.19.444887

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.

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