A distinctive ligand recognition mechanism by the human vasoactive intestinal polypeptide receptor 2

  • Nat Commun. 2022 Apr 27;13(1):2272. doi: 10.1038/s41467-022-30041-z.
Yingna Xu  #  1 ,  Wenbo Feng  #  1 ,  Qingtong Zhou  #  1 ,  Anyi Liang  2 ,  Jie Li  1 ,  Antao Dai  3 ,  Fenghui Zhao  3 ,  Jiahui Yan  3  4  5 ,  Chuan-Wei Chen  6 ,  Hao Li  6 ,  Li-Hua Zhao  4  5 ,  Tian Xia  2 ,  Yi Jiang  4  5 ,  H Eric Xu  7  8 ,  Dehua Yang  9  10  11  12 ,  Ming-Wei Wang  13  14  15  16  17  18  19
Affiliations
  • 1. Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
  • 2. School of Artificial Intelligence and Automation, Huazhong University of Science and Technology, Wuhan, 430074, China.
  • 3. The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 4. The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 5. University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 6. Research Center for Deepsea Bioresources, Sanya, Hainan, 572025, China.
  • 7. The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 8. University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
  • 9. The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 10. The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 11. University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
  • 12. Research Center for Deepsea Bioresources, Sanya, Hainan, 572025, China. [email protected].
  • 13. Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. [email protected].
  • 14. The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 15. The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 16. University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
  • 17. Research Center for Deepsea Bioresources, Sanya, Hainan, 572025, China. [email protected].
  • 18. School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. [email protected].
  • 19. Department of Chemistry, School of Science, The University of Tokyo, Tokyo, 113-0033, Japan. [email protected].
  • # Contributed equally.
PMID: 35477937 DOI: 10.1038/s41467-022-30041-z
Abstract

Class B1 of G protein-coupled receptors (GPCRs) comprises 15 members activated by physiologically important peptide Hormones. Among them, vasoactive intestinal polypeptide receptor 2 (VIP2R) is expressed in the central and peripheral nervous systems and involved in a number of pathophysiological conditions, including pulmonary arterial Hypertension, autoimmune and psychiatric disorders, in which it is thus a valuable drug target. Here, we report the cryo-electron microscopy structure of the human VIP2R bound to its endogenous ligand PACAP27 and the stimulatory G protein. Different from all reported peptide-bound class B1 GPCR structures, the N-terminal α-helix of VIP2R adopts a unique conformation that deeply inserts into a cleft between PACAP27 and the extracellular loop 1, thereby stabilizing the peptide-receptor interface. Its truncation or extension significantly decreased VIP2R-mediated cAMP accumulation. Our results provide additional information on peptide recognition and receptor activation among class B1 GPCRs and may facilitate the design of better therapeutics.