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 ...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 G 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.
EMDB-0940, PDB-6lpb: Cryo-EM structure of the human PAC1 receptor coupled to an engineered heterotrimeric G protein Method: EM (single particle) / Resolution: 3.9 Å
Source
homo sapiens (human)
rattus norvegicus (Norway rat)
unidentified (others)
bos taurus (cattle)
Keywords
SIGNALING PROTEIN/HORMONE / CLASS B GPCR / PACAP / PAC1R / SIGNALING PROTEIN-HORMONE COMPLEX
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Keywords
homo sapiens (human)
rattus norvegicus (Norway rat)
bos taurus (cattle)