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

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 con...

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Detalles Bibliográficos
Autores principales: Xu, Yingna, Feng, Wenbo, Zhou, Qingtong, Liang, Anyi, Li, Jie, Dai, Antao, Zhao, Fenghui, Yan, Jiahui, Chen, Chuan-Wei, Li, Hao, Zhao, Li-Hua, Xia, Tian, Jiang, Yi, Xu, H. Eric, Yang, Dehua, Wang, Ming-Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9046186/
https://www.ncbi.nlm.nih.gov/pubmed/35477937
http://dx.doi.org/10.1038/s41467-022-30041-z
Descripción
Sumario: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.