Abstract
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 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.
Competing Interest Statement
The authors have declared no competing interest.
