Structures of the human cholecystokinin receptors bound to agonists and antagonists

  • Nat Chem Biol. 2021 Dec;17(12):1230-1237. doi: 10.1038/s41589-021-00866-8.
Xuefeng Zhang  #  1  2 ,  Chenglin He  #  3 ,  Mu Wang  #  1  2  4 ,  Qingtong Zhou  #  5  6 ,  Dehua Yang  #  1  2  7 ,  Ya Zhu  #  1 ,  Wenbo Feng  3 ,  Hui Zhang  1  2 ,  Antao Dai  7 ,  Xiaojing Chu  1 ,  Jia Wang  7 ,  Zhenlin Yang  1 ,  Yi Jiang  1 ,  Ulrich Sensfuss  8 ,  Qiuxiang Tan  1 ,  Shuo Han  1 ,  Steffen Reedtz-Runge  8 ,  H Eric Xu  1  2 ,  Suwen Zhao  9  10 ,  Ming-Wei Wang  11  12  13  14  15  16 ,  Beili Wu  17  18  19  20 ,  Qiang Zhao  21  22  23  24
Affiliations
  • 1. State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 2. University of Chinese Academy of Sciences, Beijing, China.
  • 3. School of Pharmacy, Fudan University, Shanghai, China.
  • 4. School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • 5. iHuman Institute, ShanghaiTech University, Shanghai, China.
  • 6. Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
  • 7. The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 8. Novo Nordisk A/S, Måløv, Denmark.
  • 9. School of Life Science and Technology, ShanghaiTech University, Shanghai, China. [email protected].
  • 10. iHuman Institute, ShanghaiTech University, Shanghai, China. [email protected].
  • 11. State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 12. University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • 13. School of Pharmacy, Fudan University, Shanghai, China. [email protected].
  • 14. School of Life Science and Technology, ShanghaiTech University, Shanghai, China. [email protected].
  • 15. Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, China. [email protected].
  • 16. The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 17. State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 18. University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • 19. School of Life Science and Technology, ShanghaiTech University, Shanghai, China. [email protected].
  • 20. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. [email protected].
  • 21. State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 22. University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • 23. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. [email protected].
  • 24. Zhongshan Institute for Drug Discovery, The Institutes of Drug Discovery and Development, Chinese Aacademy of Sciences, Guangdong, China. [email protected].
  • # Contributed equally.
PMID: 34556863 DOI: 10.1038/s41589-021-00866-8
Abstract

Cholecystokinin receptors, CCKAR and CCKBR, 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 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.