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

Kazuhiro Kobayashi, Wataru Shihoya, Tomohiro Nishizawa, Francois Marie Ngako Kadji, Junken Aoki, Asuka Inoue, Osamu Nureki

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)274-280
Number of pages7
JournalNature Structural and Molecular Biology
Volume27
Issue number3
DOIs
Publication statusPublished - 2020 Mar 1

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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