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

By Yingna Xu, Wenbo Feng, Qingtong Zhou, Anyi Liang, Jie Li, Antao Dai, Fenghui Zhao, Lihua Zhao, Tian Xia, Yi Jiang, H. Eric Xu, Dehua Yang, Ming-Wei Wang

Posted 17 Sep 2021
bioRxiv DOI: 10.1101/2021.09.16.460712

Activated by physiologically important peptide hormones, class B1 G protein-coupled receptors (GPCRs) modulate key physiological functions and serve as valuable drug targets for many diseases. Among them, vasoactive intestinal polypeptide receptor 2 (VIP2R) is the last member whose full-length 3-dimensional structure has yet to be determined. VIP2R, expressed in the central and peripheral nervous systems and involved in a number of pathophysiological conditions, is implicated in pulmonary arterial hypertension, autoimmune and psychiatric disorders. 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 -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.

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