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Structural insights into ligand recognition and activation of the melanocortin-4 receptor

文献类型：期刊论文

作者Zhang, Huibing2,3,4,5,6; Chen, Li-Nan2,3,4,5,6; Yang, Dehua7,8,9; Mao, Chunyou2,3,4,5,6; Shen, Qingya2,3,4,5,6; Feng, Wenbo10; Shen, Dan-Dan2,3,4,5,6; Dai, Antao7,8; Xie, Shanshan1,11,12,13,14; Zhou, Yan7,8
刊名CELL RESEARCH
出版日期2021-08-25
页码13
ISSN号1001-0602
DOI10.1038/s41422-021-00552-3
通讯作者Wang, Ming-Wei(mwwang@simm.ac.cn) ; Zhang, Yan(zhang_yan@zju.edu.cn)
英文摘要Melanocortin-4 receptor (MC4R) plays a central role in the regulation of energy homeostasis. Its high sequence similarity to other MC receptor family members, low agonist selectivity and the lack of structural information concerning MC4R-specific activation have hampered the development of MC4R-seletive therapeutics to treat obesity. Here, we report four high-resolution structures of full-length MC4R in complex with the heterotrimeric G(s) protein stimulated by the endogenous peptide ligand alpha-MSH, FDA-approved drugs afamelanotide (Scenesse (TM)) and bremelanotide (Vyleesi (TM)), and a selective small-molecule ligand THIQ, respectively. Together with pharmacological studies, our results reveal the conserved binding mode of peptidic agonists, the distinctive molecular details of small-molecule agonist recognition underlying receptor subtype selectivity, and a distinct activation mechanism for MC4R, thereby offering new insights into G protein coupling. Our work may facilitate the discovery of selective therapeutic agents targeting MC4R.
WOS关键词CRYO-EM STRUCTURE ; ALPHA-MELANOTROPIN ; CRYSTAL-STRUCTURE ; MOLECULAR DETERMINANTS ; MC4R AGONISTS ; GS-PROTEIN ; DESIGN ; POTENT ; PHARMACOLOGY ; MECHANISM
资助项目National Natural Science Foundation of China[81922071] ; National Natural Science Foundation of China[81872915/82073904] ; National Natural Science Foundation of China[81773792/81973373] ; National Key Basic Research Program of China[2019YFA0508800] ; National Key Basic Research Program of China[2018YFA0507000] ; National Key Basic Research Program of China[2018ZX09711002-002-005] ; Zhejiang Province Science Fund for Distinguished Young Scholars[LR19H310001] ; Key R&D Projects of Zhejiang Province[2021C03039] ; National Science & Technology Major Project of China - Key New Drug Creation and Manufacturing Program[2018ZX09711002-002-005] ; National Science & Technology Major Project of China - Key New Drug Creation and Manufacturing Program[2018ZX09735-001] ; Novo Nordisk-CAS Research Fund[NNCAS-2017-1-CC]
WOS研究方向Cell Biology
语种英语
出版者SPRINGERNATURE
WOS记录号WOS:000688382800001
源URL[http://119.78.100.183/handle/2S10ELR8/297733]  
专题中国科学院上海药物研究所
通讯作者Wang, Ming-Wei; Zhang, Yan
作者单位1.Zhejiang Univ, Sch Med, Affiliated Hosp 2, Dept Cell Biol, Hangzhou, Peoples R China
2.Zhejiang Univ, Sch Med, Sir Run Run Shaw Hosp, Dept Biophys, Hangzhou, Zhejiang, Peoples R China
3.Zhejiang Univ, Sch Med, Sir Run Run Shaw Hosp, Dept Pathol, Hangzhou, Zhejiang, Peoples R China
4.Zhejiang Univ, Liangzhu Lab, Med Ctr, Hangzhou, Zhejiang, Peoples R China
5.Zhejiang Univ, Sch Med, MOE Frontier Sci Ctr Brain Res & Brain Machine In, Hangzhou, Zhejiang, Peoples R China
6.Key Lab Immun & Inflammatory Dis Zhejiang Prov, Hangzhou, Zhejiang, Peoples R China
7.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai, Peoples R China
8.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, Shanghai, Peoples R China
9.Univ Chinese Acad Sci, Beijing, Peoples R China
10.Fudan Univ, Sch Pharm, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Huibing,Chen, Li-Nan,Yang, Dehua,et al. Structural insights into ligand recognition and activation of the melanocortin-4 receptor[J]. CELL RESEARCH,2021:13.
APA Zhang, Huibing.,Chen, Li-Nan.,Yang, Dehua.,Mao, Chunyou.,Shen, Qingya.,...&Zhang, Yan.(2021).Structural insights into ligand recognition and activation of the melanocortin-4 receptor.CELL RESEARCH,13.
MLA Zhang, Huibing,et al."Structural insights into ligand recognition and activation of the melanocortin-4 receptor".CELL RESEARCH (2021):13.

入库方式： OAI收割

来源：上海药物研究所

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