Cryo-EM structure of the human PAC1 receptor coupled to an engineered heterotrimeric G protein.

Nature Structural & Molecular Biology
Kazuhiro KobayashiOsamu Nureki

Abstract

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic neuropeptide hormone. The PACAP receptor PAC1R, which belongs to the class B G-protein-coupled receptors (GPCRs), is a drug target for mental disorders and dry eye syndrome. Here, we present a cryo-EM structure of human PAC1R bound to PACAP and an engineered Gs heterotrimer. The structure revealed that transmembrane helix TM1 plays an essential role in PACAP recognition. The extracellular domain (ECD) of PAC1R tilts by ~40° compared with that of the glucagon-like peptide-1 receptor (GLP-1R) and thus does not cover the peptide ligand. A functional analysis demonstrated that the PAC1R ECD functions as an affinity trap and is not required for receptor activation, whereas the GLP-1R ECD plays an indispensable role in receptor activation, illuminating the functional diversity of the ECDs in class B GPCRs. Our structural information will facilitate the design and improvement of better PAC1R agonists for clinical applications.

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Citations

May 7, 2020·The Journal of Biological Chemistry·Rulue ChangPatrick M Sexton
Oct 4, 2020·Biochemical and Biophysical Research Communications·Satoshi FukuharaOsamu Nureki
Apr 13, 2021·Frontiers in Molecular Biosciences·Chenyi LiaoJianing Li
Oct 17, 2020·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Cosmin I Ciotu, Michael J M Fischer
Apr 17, 2020·ACS Pharmacology & Translational Science·Lee E EidenLimei Zhang

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Datasets Mentioned

BETA
AK290046

Methods Mentioned

BETA
gel filtration
NMR
X-ray
transfection
flow cytometry

Software Mentioned

RELION
CTFFIND
GeneArt
MolProbity
Prism
FlowJo
MotionCor2
UCSF Chimera
Rosetta
GraphPad Prism

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