小柯机器人

中国科学院上海药物研究所H. Eric Xu、Li-Hua Zhao研究组，揭示了特异性细胞内激动剂激活保守B类G蛋白偶联受体（GPCR）的机制。该项研究成果发表在2023年7月31日出版的《自然》上。

研究人员解析了人甲状旁腺激素受体1（PTH1R）与刺激性G蛋白（Gs）和小分子激动剂PCO371复合物的高分辨率结构，并发现了PCO371在PTH1R与Gs细胞质界面处的特殊结合模式。PCO371的结合位点完全不同于所有先前已报道的小分子或肽配体与GPCR的结合位点。构成PCO371结合口袋的残基在B类GPCR中保守，PTH2型受体（PTH2R）中的单突变和GLP-1R中两个残基突变可将这些受体转化为PCO371的激活剂。功能测定显示，PCO371是一种G蛋白偏倚激动剂，在促进PTH1R介导的阻滞蛋白信号传导方面存在缺陷。

总之，这些结果揭示了一个独特的结合位点，可用于设计针对PTH1R和B类GPCR其他成员的小分子激活剂，并揭示了特异性靶向G蛋白活化而非阻滞蛋白信号传导的受体构象。该结构有助于设计不同类型的B类GPCR小分子激动剂，以用于各种适应症的治疗。

据悉，B类GPCR是重要的药物靶点，其包括胰高血糖素样受体1（GLP-1R）和PTH1R。已开发出靶向这些受体的注射肽药物，但口服小分子药物正处在研发阶段。

附：英文原文

Title: Conserved class B GPCR activation by a biased intracellular agonist

Author: Zhao, Li-Hua, He, Qian, Yuan, Qingning, Gu, Yimin, He, Xinheng, Shan, Hong, Li, Junrui, Wang, Kai, Li, Yang, Hu, Wen, Wu, Kai, Shen, Jianhua, Xu, H. Eric

Issue&Volume: 2023-07-31

Abstract: Class B G protein-coupled receptors (GPCRs), including glucagon-like receptor 1 (GLP-1R) and parathyroid hormone receptor 1 (PTH1R), are important drug targets1-5. Injectable peptide drugs targeting these receptors have been developed but orally available small molecule drugs are hotly pursued 6,7. Here we report the high-resolution structure of the human PTH1R in complex with the stimulatory G protein (Gs) and a small molecule agonist, PCO371, which reveals an unexpected binding mode of PCO371 at the cytoplasmic interface of PTH1R with Gs. The binding site of PCO371 is totally different from all binding sites previously reported for small molecules or peptide ligands in GPCRs. Residues that make up the PCO371 binding pocket are conserved in class B GPCRs and a single mutation in PTH type 2 receptor (PTH2R) and two residue mutations in GLP-1R convert these receptors to respond to PCO371 activation. Functional assays reveal that PCO371 is a G-protein biased agonist that is defective in promoting PTH1R-mediated arrestin signaling. Together, these results uncover a distinct binding site for designing small molecule agonists for PTH1R and possible other members of class B GPCRs and define a receptor conformation that is only specific for G protein activation but not arrestin signaling. These insights should facilitate the design of distinct types of class B GPCR small molecule agonists for various therapeutic indications.

DOI: 10.1038/s41586-023-06467-w

Source: https://www.nature.com/articles/s41586-023-06467-w

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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