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Structural insights into ligand recognition and subtype selectivity of the human melanocortin-3 and melanocortin-5 receptors

文献类型：期刊论文

作者Feng, Wenbo1; Zhou, Qingtong1; Chen, Xianyue2; Dai, Antao3,4; Cai, Xiaoqing3,4; Liu, Xiao1; Zhao, Fenghui3,4; Chen, Yan1; Ye, Chenyu1; Xu, Yingna1
刊名CELL DISCOVERY
出版日期2023-07-31
卷号9期号:1页码:15
DOI10.1038/s41421-023-00586-4
通讯作者Yang, Dehua(dhyang@simm.ac.cn) ; Wang, Ming-Wei(mwwang@simm.ac.cn)
英文摘要Members of the melanocortin receptor (MCR) family that recognize different melanocortin peptides mediate a broad spectrum of cellular processes including energy homeostasis, inflammation and skin pigmentation through five MCR subtypes (MC1R-MC5R). The structural basis of subtype selectivity of the endogenous agonist & gamma;-MSH and non-selectivity of agonist & alpha;-MSH remains elusive, as the two agonists are highly similar with a conserved HFRW motif. Here, we report three cryo-electron microscopy structures of MC3R-G(s) in complex with & gamma;-MSH and MC5R-G(s) in the presence of & alpha;-MSH or a potent synthetic agonist PG-901. The structures reveal that & alpha;-MSH and & gamma;-MSH adopt a "U-shape" conformation, penetrate into the wide-open orthosteric pocket and form massive common contacts with MCRs via the HFRW motif. The C-terminus of & gamma;-MSH occupies an MC3R-specific complementary binding groove likely conferring subtype selectivity, whereas that of & alpha;-MSH distances itself from the receptor with neglectable contacts. PG-901 achieves the same potency as & alpha;-MSH with a shorter length by rebalancing the recognition site and mimicking the intra-peptide salt bridge in & alpha;-MSH by cyclization. Solid density confirmed the calcium ion binding in MC3R and MC5R, and the distinct modulation effects of divalent ions were demonstrated. Our results provide insights into ligand recognition and subtype selectivity among MCRs, and expand the knowledge of signal transduction among MCR family members.
WOS关键词MOLECULAR-CLONING ; PROOPIOMELANOCORTIN ; EXPRESSION ; PEPTIDES ; GENE ; MELANOTROPIN ; VALIDATION ; MECHANISM ; EVOLUTION ; AGONISM
资助项目National Natural Science Foundation of China[81872915] ; National Natural Science Foundation of China[82073904] ; National Natural Science Foundation of China[82273961] ; National Natural Science Foundation of China[82273985] ; National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[81973373] ; National Natural Science Foundation of China[21704064] ; National Science and Technology Major Project of China-Key New Drug Creation and Manufacturing Program[2018ZX09735-001] ; National Science and Technology Major Project of China-Key New Drug Creation and Manufacturing Program[2018ZX09711002-002-005] ; National Key Basic Research Program of China[ZDKJ2021028] ; Hainan Provincial Major Science and Technology Project[21JC1401600] ; Shanghai Municipality Science and Technology Development Fund[23XD1400900] ; Shanghai Municipality Science and Technology Development Fund[2021ZD0203400] ; STI2030-Major Project ; [2018YFA0507000]
WOS研究方向Cell Biology
语种英语
出版者SPRINGERNATURE
WOS记录号WOS:001040356900001
源URL[http://119.78.100.183/handle/2S10ELR8/306809]  
专题中国科学院上海药物研究所
通讯作者Yang, Dehua; Wang, Ming-Wei
作者单位1.Fudan Univ, Sch Basic Med Sci, Dept Pharmacol, Shanghai, Peoples R China
2.Res Ctr Deepsea Bioresources, Sanya, Hainan, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai, Peoples R China
5.Univ Chinese Acad Sci, Beijing, Peoples R China
6.Univ Tokyo, Sch Sci, Dept Chem, Tokyo, Japan
7.Hainan Med Univ, Sch Pharm, Haikou, Hainan, Peoples R China
推荐引用方式
GB/T 7714		 Feng, Wenbo,Zhou, Qingtong,Chen, Xianyue,et al. Structural insights into ligand recognition and subtype selectivity of the human melanocortin-3 and melanocortin-5 receptors[J]. CELL DISCOVERY,2023,9(1):15.
APA Feng, Wenbo.,Zhou, Qingtong.,Chen, Xianyue.,Dai, Antao.,Cai, Xiaoqing.,...&Wang, Ming-Wei.(2023).Structural insights into ligand recognition and subtype selectivity of the human melanocortin-3 and melanocortin-5 receptors.CELL DISCOVERY,9(1),15.
MLA Feng, Wenbo,et al."Structural insights into ligand recognition and subtype selectivity of the human melanocortin-3 and melanocortin-5 receptors".CELL DISCOVERY 9.1(2023):15.

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来源：上海药物研究所

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