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

Yingna Xu, Wenbo Feng, Qingtong Zhou, Anyi Liang, Jie Li, Antao Dai, Fenghui Zhao, Jiahui Yan, Chuan-Wei Chen, Hao Li, Li-Hua Zhao, Tian Xia, Yi Jiang, H. Eric Xu (), Dehua Yang () and Ming-Wei Wang ()
Additional contact information
Yingna Xu: Fudan University
Wenbo Feng: Fudan University
Qingtong Zhou: Fudan University
Anyi Liang: Huazhong University of Science and Technology
Jie Li: Fudan University
Antao Dai: Chinese Academy of Sciences
Fenghui Zhao: Chinese Academy of Sciences
Jiahui Yan: Chinese Academy of Sciences
Chuan-Wei Chen: Research Center for Deepsea Bioresources
Hao Li: Research Center for Deepsea Bioresources
Li-Hua Zhao: Chinese Academy of Sciences
Tian Xia: Huazhong University of Science and Technology
Yi Jiang: Chinese Academy of Sciences
H. Eric Xu: Chinese Academy of Sciences
Dehua Yang: Chinese Academy of Sciences
Ming-Wei Wang: Fudan University

Nature Communications, 2022, vol. 13, issue 1, 1-10

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30041-z

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