Structural insights into human brain-gut peptide cholecystokinin receptors

  • Cell Discov. 2022 Jun 7;8(1):55. doi: 10.1038/s41421-022-00420-3.
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. [email protected].
  • 6. Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, Zhejiang, China. [email protected].
  • 7. Zheijang Provincial Key Laboratory of Immunity and Inflammatory Diseases, Hangzhou, Zhejiang, China. [email protected].
  • 8. Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. [email protected].
  • 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. [email protected].
  • 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. [email protected].
  • # Contributed equally.
PMID: 35672283 DOI: 10.1038/s41421-022-00420-3
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 Gs and Gq, whereas CCK2R primarily couples to Gq. Here we report the cryo-electron microscopy (cryo-EM) structures of CCK1R-Gs signaling complexes liganded either by sulfated cholecystokinin octapeptide (CCK-8) or a CCK1R-selective small-molecule SR146131, and CCK2R-Gq 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.