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Abstract：
The rhodopsin-like receptor GPR119 plays a crucial role in glucose homeostasis and is an emerging target for the treatment of type 2 diabetes mellitus. In this study, we analyzed the structure of GPR119 with the agonist APD597 bound and in complex with the downstream G protein trimer by single particle cryo-electron microscopy (cryo-EM). Structural comparison in combination with function assay revealed the conservative and specific effects of different kinds of GPR119 agonists. The activation mechanism of GPR119 was analyzed by comparing the conformational changes between the inactive and active states. The interaction between APD597 derivatives and synthetic agonists with GPR119 was analyzed by molecular docking technique, and the necessary structural framework was obtained. The above conclusions can provide structural and theoretical basis for the development of therapeutic drugs for type 2 diabetes mellitus.
摘要：
视紫红质样受体GPR119在葡萄糖稳态中起着至关重要的作用，并且是治疗2型糖尿病的新兴靶标。在这项研究中,我们通过单粒子冷冻电子显微镜(cryo-EM)分析了GPR119与激动剂APD597结合并与下游G蛋白三聚体复合的结构.结合功能测定的结构比较揭示了不同类型GPR119激动剂的保守和特异性作用。通过比较非活性状态和活性状态之间的构象变化，分析了GPR119的激活机制。通过分子对接技术分析了APD597衍生物和合成激动剂与GPR119的相互作用，并获得了必要的结构框架。以上结论可为开发2型糖尿病治疗药物提供结构和理论依据。
