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_s 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多肽（PACAP）是一种多效神经肽激素。PACAP受体PAC1R属于B类G蛋白偶联受体（GPCR），是精神疾病和干眼症的药物靶标。这里，我们提出势必PACAP人类PAC1R的冷冻电镜结构和工程改造的G ^_小号异三聚体。该结构表明跨膜螺旋TM1在PACAP识别中起重要作用。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〜40°，因此不覆盖肽配体。功能分析表明，PAC1R ECD充当亲和阱，并不是受体激活所必需的，而GLP-1R ECD在受体激活中起着不可或缺的作用，从而阐明了B类GPCR中ECD的功能多样性。我们的结构信息将有助于为临床应用设计和改进更好的PAC1R激动剂。