GPR20 是一种孤儿 G 蛋白偶联受体 (GPCR)，在肠道组织中表现出显着表达，是治疗胃肠道间质瘤的潜在治疗靶点。 GPR20 与 Gi 偶联时表现出高组成活性。尽管 GPCR 组成型激活具有药理学重要性，但其机制长期以来仍不清楚。在本研究中，我们通过大规模无偏分子动力学模拟探索了GPR20的本构激活机制。我们的结果揭示了涉及细胞外和细胞内结构域的组成型激活的 GPCR 信号转导的变构性质。此外，GPR20 的组成型活性状态需要 N 端帽和 Gi 蛋白。 GPR20 的 N 末端帽的功能类似于激动剂，并介导长程激活构象转变。与之前的研究一起，本研究增强了我们对孤儿受体自激活机制的认识，促进了针对 GPR20 的药物发现工作。© 2024。作者获得上海药物研究所独家许可，中国科学院、中国药理学会。

GPR20, an orphan G protein-coupled receptor (GPCR), shows significant expression in intestinal tissue and represents a potential therapeutic target to treat gastrointestinal stromal tumors. GPR20 performs high constitutive activity when coupling with Gi. Despite the pharmacological importance of GPCR constitutive activation, determining the mechanism has long remained unclear. In this study, we explored the constitutive activation mechanism of GPR20 through large-scale unbiased molecular dynamics simulations. Our results unveil the allosteric nature of constitutively activated GPCR signal transduction involving extracellular and intracellular domains. Moreover, the constitutively active state of the GPR20 requires both the N-terminal cap and Gi protein. The N-terminal cap of GPR20 functions like an agonist and mediates long-range activated conformational shift. Together with the previous study, this study enhances our knowledge of the self-activation mechanism of the orphan receptor, facilitates the drug discovery efforts that target GPR20.© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.