Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Bunkyo, Tokyo, Japan.
Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan.
Nat Struct Mol Biol. 2020 Mar;27(3):274-280. doi: 10.1038/s41594-020-0386-8. Epub 2020 Mar 9.
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.
垂体腺苷酸环化酶激活肽（PACAP）是一种多功能神经肽激素。PAC1R 是 PACAP 受体，属于 B 类 G 蛋白偶联受体（GPCR），是精神障碍和干眼症综合征的药物靶点。在这里，我们展示了与人 PAC1R 结合的 PACAP 和工程化 G 三聚体的冷冻电镜结构。该结构揭示了跨膜螺旋 TM1 在 PACAP 识别中起着重要作用。与胰高血糖素样肽-1 受体（GLP-1R）相比，PAC1R 的细胞外结构域（ECD）倾斜约 40°，因此不会覆盖肽配体。功能分析表明，PAC1R ECD 作为亲和力陷阱发挥作用，对于受体激活并非必需，而 GLP-1R ECD 在受体激活中起着不可或缺的作用，阐明了 B 类 GPCR 中 ECD 的功能多样性。我们的结构信息将有助于设计和改进更好的 PAC1R 激动剂，用于临床应用。
