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  2. 上海药物研究所
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  4. 新药研究国家重点实验室
Structural basis of signaling regulation of the human melanocortin-2 receptor by MRAP1

文献类型：期刊论文

作者Luo, Ping3; Feng, Wenbo4; Ma, Shanshan3; Dai, Antao5; Wu, Kai3; Chen, Xianyue6; Yuan, Qingning3; Cai, Xiaoqing5; Yang, Dehua1,5,6; Wang, Ming-Wei1,4,5,6
刊名CELL RESEARCH
出版日期2023-01-02
页码9
ISSN号1001-0602
DOI10.1038/s41422-022-00751-6
通讯作者Wang, Ming-Wei(mwwang@simm.ac.cn) ; Eric Xu, H.(eric.xu@simm.ac.cn) ; Jiang, Yi(yjiang@lglab.ac.cn)
英文摘要G protein-coupled receptors (GPCRs) are regulated by various downstream proteins, of which the melanocortin receptor accessory protein 1 (MRAP1) is closely involved in the regulation of melanocortin receptor 2 (MC2R). Assisted by MRAP1, MC2R responds to adrenocorticotropic hormone (ACTH) and stimulates glucocorticoid biogenesis and cortisol secretion. MC2R activation plays an essential role in the hypothalamic-pituitary-adrenal (HPA) axis that regulates stress response, while its dysfunction causes glucocorticoid insufficiency- or cortisol excess-associated disorders. Here, we present a cryo-electron microscopy (cryo-EM) structure of the ACTH-bound MC2R-G(s)-MRAP1 complex. Our structure, together with mutagenesis analysis, reveals a unique sharp kink at the extracellular region of MRAP1 and the 'seat-belt' effect of MRAP1 on stabilizing ACTH binding and MC2R activation. Mechanisms of ACTH recognition by MC2R and receptor activation are also demonstrated. These findings deepen our understanding of GPCR regulation by accessory proteins and provide valuable insights into the ab initio design of therapeutic agents targeting MC2R.
WOS关键词FAMILIAL GLUCOCORTICOID DEFICIENCY ; ACCESSORY PROTEIN ; MC2 RECEPTOR ; TRAFFICKING ; GENES ; MODEL
资助项目National Natural Science Foundation[32171187] ; National Natural Science Foundation[82121005] ; National Natural Science Foundation[32130022] ; National Natural Science Foundation[81872915] ; National Natural Science Foundation[81773792] ; National Natural Science Foundation[81973373] ; Ministry of Science and Technology (China) grants[2018YFA0507002] ; Shanghai Municipal Science and Technology Major Project[2019SHZDZX02] ; CAS Strategic Priority Research Program[XDB37030103] ; Shanghai Municipal Science and Technology Major Project
WOS研究方向Cell Biology
语种英语
出版者SPRINGERNATURE
WOS记录号WOS:000906399000006
源URL[http://119.78.100.183/handle/2S10ELR8/303920]  
专题新药研究国家重点实验室
通讯作者Wang, Ming-Wei; Eric Xu, H.; Jiang, Yi
作者单位1.Univ Chinese Acad Sci, Beijing, Peoples R China
2.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai, Peoples R China
4.Fudan Univ, Sch Basic Med Sci, Dept Pharmacol, Shanghai, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai, Peoples R China
6.Res Ctr Deepsea Bioresources, Sanya, Hainan, Peoples R China
7.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
8.Lingang Lab, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Luo, Ping,Feng, Wenbo,Ma, Shanshan,et al. Structural basis of signaling regulation of the human melanocortin-2 receptor by MRAP1[J]. CELL RESEARCH,2023:9.
APA Luo, Ping.,Feng, Wenbo.,Ma, Shanshan.,Dai, Antao.,Wu, Kai.,...&Jiang, Yi.(2023).Structural basis of signaling regulation of the human melanocortin-2 receptor by MRAP1.CELL RESEARCH,9.
MLA Luo, Ping,et al."Structural basis of signaling regulation of the human melanocortin-2 receptor by MRAP1".CELL RESEARCH (2023):9.

入库方式： OAI收割

来源：上海药物研究所

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