Cryo-EM structure of the human PAC1 receptor coupled to an engineered heterotrimeric G protein
Cryo-EM structure of the human PAC1 receptor coupled to an engineered heterotrimeric G protein
复制标题
DOI：
10.1038/s41594-020-0386-8
复制
发表时间：
2020-03-01
影响因子：
16.8
通讯作者：
Nureki, Osamu
中科院分区：
文献类型：
--
作者：
Kobayashi, Kazuhiro;Shihoya, Wataru;Nureki, Osamu
人PAC 1 R受体与其神经肽配体PACAP及G（s）复合物结合的冷冻电镜结构揭示了PACAP的识别模式，并提示B类GPCR中胞外结构域的功能多样性。PACAP受体PAC 1 R属于B类G蛋白偶联受体（GPCR），是精神障碍和干眼综合征的药物靶点。在这里，我们提出了一个cryo-EM结构的人PAC 1 R结合PACAP和工程G（S）异源三聚体。该结构揭示了跨膜螺旋TM 1在PACAP识别中起重要作用。与胰高血糖素样肽-1受体（GLP-1 R）相比，PAC 1 R的胞外结构域（ECD）倾斜约40度，因此不覆盖肽配体。功能分析表明，PAC 1 R ECD作为亲和陷阱发挥作用，并且不是受体活化所必需的，而GLP-1 R ECD在受体活化中发挥不可或缺的作用，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PAC 1 R激动剂用于临床应用。
Cryo-EM structure of the human PAC1R receptor bound to its neuropeptide ligand PACAP and to an engineered G(s) complex reveals the mode of PACAP recognition and suggests functional diversity of the extracellular domains in class B GPCRs.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 degrees 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.