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, Lihua Zhao, Tian Xia, Yi Jiang, H. Eric Xu, Dehua Yang, Ming‐Wei Wang
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.