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

• クライオ電子顕微鏡を用いた単粒子解析法によって構造未知であったヒト由来PAC1受容体とGタンパク質との複合体構造が明らかとなった。
• 今後は、本構造情報を活用した、PAC1受容体の膜貫通部位と選択的に相互作用できる低分子薬剤の開発が期待される。

Abstract

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic neuropeptide hormone functioning in the central nervous system and peripheral tissues. 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-electron microscopy structure of human PAC1R bound to PACAP and an engineered Gs heterotrimer. The structure revealed that TM1 plays an essential role in PACAP recognition. The ECD (extracellular domain) of PAC1R tilts by ~40° as compared to that of the glucagon-like peptide-1 receptor (GLP1R), 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 GLP1R-ECD plays an indispensable role in receptor activation, illuminating the functional diversity of the ECDs in the class B GPCRs. Our structural information will facilitate the design and improvement of better PAC1R agonists for clinical applications.

分解能

4.0Å ~ 4.5Å

Citation

Kobayashi, W. Shihoya, T. Nishizawa, F. M. N. Kadji, J. Aoki, A. Inoue and O. Nureki. Nat. Struct. Mol. Biol. 27:274-280 (2020).