Cell biology

Biology

Receptor

Biochemistry

G protein

G protein-coupled receptor

Heterotrimeric G protein

Chemistry

Transmembrane domain

Biophysics

Nature Structural & Molecular Biology

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. Cryo-EM structure of the human PAC1R receptor bound to its neuropeptide ligand PACAP and to an engineered Gs complex reveals the mode of PACAP recognition and suggests functional diversity of the extracellular domains in class B GPCRs.

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