Li Hao, Zhang Jinyi, Yu Yanan, Luo Feng, Wu Lijie, Liu Junlin, Chen Na, Liu Zhijie, Hua Tian
iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
Sci Bull (Beijing). 2023 Jan 15;68(1):95-104. doi: 10.1016/j.scib.2022.12.023. Epub 2022 Dec 26.
G protein-coupled receptor 12 (GPR12) is an orphan G protein-coupled receptor that is highly expressed in the thalamus of the brain and plays a vital role in driving thalamocortical functions in short-term memory. GPR12 performs high constitutive activity and couples with G, increasing the intracellular cyclic adenosine monophosphate (cAMP) level when it is expressed. However, exploitation for drug development is limited since it is unclear how GPR12 initiates self-activation and signal transduction, and whether it can be modulated by endogenous or synthetic ligands. Here, we report the cryo-electron microscopy structure of the GPR12-G complex in the absence of agonists. Our structure reveals the key determinants for the intrinsically high basal activity of GPR12, including extracellular loop 2 partially occupying the orthosteric binding pocket, a tight-packed TM1 and TM7, and unique activation-related residues in TM6 and TM7. Together with mutagenesis data, this study will improve our understanding of the function and self-activation of the orphan receptor GPR12, enable the identification of endogenous ligands, and guide drug discovery efforts that target GPR12.
G蛋白偶联受体12（GPR12）是一种孤儿G蛋白偶联受体，在大脑丘脑高度表达，在驱动短期记忆中的丘脑皮质功能方面发挥着至关重要的作用。GPR12具有较高的组成性活性，表达时与G蛋白偶联，增加细胞内环磷酸腺苷（cAMP）水平。然而，由于尚不清楚GPR12如何启动自我激活和信号转导，以及它是否能被内源性或合成配体调节，其在药物开发中的应用受到限制。在此，我们报道了无激动剂情况下GPR12-G复合物的冷冻电镜结构。我们的结构揭示了GPR12固有高基础活性的关键决定因素，包括部分占据正构结合口袋的细胞外环2、紧密堆积的跨膜螺旋1（TM1）和跨膜螺旋7（TM7），以及TM6和TM7中独特的激活相关残基。结合诱变数据，本研究将增进我们对孤儿受体GPR12功能和自我激活的理解，有助于鉴定内源性配体，并指导针对GPR12的药物研发工作。
