Structural insight into the constitutive activity of human orphan receptor GPR12

doi:10.1016/j.scib.2022.12.023

	Structural insight into the constitutive activity of human orphan receptor GPR12
	Li, Hao1,2 ; Zhang, Jinyi1,2 ; Yu, Yanan1,2 ; Luo, Feng1 ; Wu, Lijie1 ; Liu, Junlin1 ; Chen, Na1 ; Liu, Zhijie1,2 ; Hua, Tian1,2
	2023-01-15
发表期刊	SCIENCE BULLETIN (IF:18.8[JCR-2023],15.8[5-Year])
ISSN	2095-9273
EISSN	2095-9281
卷号	68 期号:1 页码:95-104
DOI	10.1016/j.scib.2022.12.023
摘要	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 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-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. © 2022 Science China Press
关键词	Electron microscopes Ligands Proteins Signal transduction Adenosine monophosphate Constitutive activation Cryo-electron microscopy Cryo-electron microscopy structure Cyclic adenosine Cyclic adenosine monophosphate G protein coupled receptors G protein-coupled receptor 12 Orphan receptor Self-activation
收录类别	EI ; SCOPUS
语种	英语
出版者	Elsevier B.V.
EI入藏号	20230213377137
EI主题词	Chemical activation
EI分类号	461.9 Biology ; 801.4 Physical Chemistry ; 802.2 Chemical Reactions ; 804 Chemical Products Generally ; 804.1 Organic Compounds
原始文献类型	Journal article (JA)
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/282010
专题	生命科学与技术学院_博士生 iHuman研究所 iHuman研究所_公共科研平台_昆虫细胞培养平台 iHuman研究所_PI研究组_刘志杰组 iHuman研究所_科学装置(X)_膜蛋白同步辐射线站 iHuman研究所_PI研究组_华甜组
通讯作者	Liu, Zhijie
作者单位	1.iHuman Institute, ShanghaiTech University, Shanghai; 201210, China; 2.School of Life Science and Technology, ShanghaiTech University, Shanghai; 201210, China
第一作者单位	iHuman研究所; 生命科学与技术学院
通讯作者单位	iHuman研究所; 生命科学与技术学院
第一作者的第一单位	iHuman研究所
推荐引用方式 GB/T 7714	Li, Hao,Zhang, Jinyi,Yu, Yanan,et al. Structural insight into the constitutive activity of human orphan receptor GPR12[J]. SCIENCE BULLETIN,2023,68(1):95-104.
APA	Li, Hao.,Zhang, Jinyi.,Yu, Yanan.,Luo, Feng.,Wu, Lijie.,...&Hua, Tian.(2023).Structural insight into the constitutive activity of human orphan receptor GPR12.SCIENCE BULLETIN,68(1),95-104.
MLA	Li, Hao,et al."Structural insight into the constitutive activity of human orphan receptor GPR12".SCIENCE BULLETIN 68.1(2023):95-104.