Structural insight into the constitutive activity of human orphan receptor GPR12
Structural insight into the constitutive activity of human orphan receptor GPR12
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人类孤儿受体 GPR12 组成活性的结构洞察
DOI：
10.1016/j.scib.2022.12.023
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发表时间：
2023-01-20
期刊：
影响因子：
18.9
通讯作者：
Hua, Tian
中科院分区：
文献类型：
--
作者：
Li, Hao;Zhang, Jinyi;Hua, Tian
G蛋白偶联受体12(GPR12)是一种孤立的G蛋白偶联受体，在大脑丘脑中高表达，在短期记忆的丘脑皮质功能中起着至关重要的作用。GPR12具有很高的结构活性，并与Gs偶联，在表达时增加细胞内环磷酸腺苷(CAMP)的水平。然而，由于GPR12如何启动自身激活和信号转导，以及GPR12是否受内源性或合成配体的调节，其药物开发受到限制。在这里，我们报告了在没有激动剂的情况下GPR12-Gs复合体的冷冻电子显微镜结构。我们的结构揭示了GPR12内在高基础活性的关键决定因素，包括细胞外环2部分占据正位结合口袋，紧密排列的TM1和TM7，以及TM6和TM7中独特的激活相关残基。结合突变数据，这项研究将提高我们对孤儿受体GPR12的功能和自我激活的理解，使内源性配体的识别成为可能，并指导针对GPR12的药物开发工作。(C)2022年科学中国出版社。爱思唯尔出版公司(Elsevier B.V.)
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 Gs, increasing the intracellular cyc-lic adenosine monophosphate (cAMP) level when it is expressed. However, exploitation for drug devel-opment 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-Gs 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. (c) 2022 Science China Press. Published by Elsevier B.V.