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- Title
A distinctive ligand recognition mechanism by the human vasoactive intestinal polypeptide receptor 2.
- Authors
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
- 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. Vasoactive intestinal polypeptide receptor 2 (VIP2R) is involved in immunity. Here, the authors report two cryo-EM structures of the VIP2R–Gs in complex with the endogenous peptide ligand PACAP27, revealing a unique interaction mode between PACAP27 and the receptor, stabilized by the N-terminal α-helix of VIP2R.
- Subjects
VASOACTIVE intestinal peptide; PITUITARY adenylate cyclase activating polypeptide; PEPTIDE hormones; PULMONARY arterial hypertension; PERIPHERAL nervous system; PEPTIDES; G protein coupled receptors
- Publication
Nature Communications, 2022, Vol 13, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-30041-z