6LPB

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

Summary for 6LPB

• Entry DOI: 10.2210/pdb6lpb/pdb
• EMDB information: 0940
• Descriptor: Pituitary adenylate cyclase-activating polypeptide, Pituitary adenylate cyclase-activating polypeptide type I receptor, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (6 entities in total)
• Functional Keywords: class b gpcr, pacap, pac1r, signaling protein-hormone complex, signaling protein/hormone
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 141495.37

Authors

Kobayashi, K.,Shihoya, W.,Nishizawa, T.,Nureki, O. (deposition date: 2020-01-09, release date: 2020-03-11, Last modification date: 2024-10-09)

Primary citation

Kobayashi, K.,Shihoya, W.,Nishizawa, T.,Kadji, F.M.N.,Aoki, J.,Inoue, A.,Nureki, O.
Cryo-EM structure of the human PAC1 receptor coupled to an engineered heterotrimeric G protein.
Nat.Struct.Mol.Biol., 27:274-280, 2020

PubMed 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 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.

PubMed: 32157248
DOI: 10.1038/s41594-020-0386-8

Experimental method

ELECTRON MICROSCOPY (3.9 Å)