Structural insights into human brain-gut peptide cholecystokinin receptors

Yu Ding; Huibing Zhang; Yu-Ying Liao; Li-Nan Chen; Su-Yu Ji; Jiao Qin; Chunyou Mao; Dan-Dan Shen; Lin Lin; Hao Wang; Yan Zhang; Xiao-Ming Li

doi:10.1038/s41421-022-00420-3

Structural insights into human brain-gut peptide cholecystokinin receptors

Cell Discov. 2022 Jun 7;8(1):55. doi: 10.1038/s41421-022-00420-3.

Authors

Yu Ding^#^{1

2}, Huibing Zhang^#^{3

4}, Yu-Ying Liao^#^{1

2}, Li-Nan Chen^#^{3

4}, Su-Yu Ji^#^{3

4}, Jiao Qin^{3

4}, Chunyou Mao^{3

4}, Dan-Dan Shen^{3

4}, Lin Lin^{1

2}, Hao Wang^{1

2}, Yan Zhang^{5

6

7}, Xiao-Ming Li^{8

9

10}

Affiliations

¹ Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
² NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Center of Brain Science and Brain-machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
³ Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
⁴ Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, Zhejiang, China.
⁵ Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. zhang_yan@zju.edu.cn.
⁶ Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, Zhejiang, China. zhang_yan@zju.edu.cn.
⁷ Zheijang Provincial Key Laboratory of Immunity and Inflammatory Diseases, Hangzhou, Zhejiang, China. zhang_yan@zju.edu.cn.
⁸ Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. lixm@zju.edu.cn.
⁹ NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Center of Brain Science and Brain-machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang, China. lixm@zju.edu.cn.
¹⁰ Center for Brain Science and Brain-Inspired Intelligence, Research Units for Emotion and Emotion Disorders, Chinese Academy of Medical Sciences, China/Guangdong-Hong Kong-Macao Greater Bay Area, Joint Institute for Genetics and Genome Medicine between Zhejiang University and University of Toronto, Hangzhou, Zhejiang, China. lixm@zju.edu.cn.

^# Contributed equally.

Abstract

The intestinal hormone and neuromodulator cholecystokinin (CCK) receptors CCK1R and CCK2R act as a signaling hub in brain-gut axis, mediating digestion, emotion, and memory regulation. CCK receptors exhibit distinct preferences for ligands in different posttranslational modification (PTM) states. CCK1R couples to G_s and G_q, whereas CCK2R primarily couples to G_q. Here we report the cryo-electron microscopy (cryo-EM) structures of CCK1R-G_s signaling complexes liganded either by sulfated cholecystokinin octapeptide (CCK-8) or a CCK1R-selective small-molecule SR146131, and CCK2R-G_q complexes stabilized by either sulfated CCK-8 or a CCK2R-selective ligand gastrin-17. Our structures reveal a location-conserved yet charge-distinct pocket discriminating the effects of ligand PTM states on receptor subtype preference, the unique pocket topology underlying selectivity of SR146131 and gastrin-17, the conformational changes in receptor activation, and key residues contributing to G protein subtype specificity, providing multiple structural templates for drug design targeting the brain-gut axis.