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DOI	10.1126/science.aaz8995
	Determination of the melanocortin-4 receptor structure identifies Ca2+ as a cofactor for ligand binding
	Yu J.; Gimenez L.E.; Hernandez C.C.; Wu Y.; Wein A.H.; Han G.W.; McClary K.; Mittal S.R.; Burdsall K.; Stauch B.; Wu L.; Stevens S.N.; Peisley A.; Williams S.Y.; Chen V.; Millhauser G.L.; Zhao S.; Cone R.D.; Stevens R.C.
发表日期	2020
ISSN	0036-8075
起始页码	428
结束页码	433
卷号	368 期号:6489
英文摘要	The melanocortin-4 receptor (MC4R) is involved in energy homeostasis and is an important drug target for syndromic obesity. We report the structure of the antagonist SHU9119-bound human MC4R at 2.8-angstrom resolution. Ca2+ is identified as a cofactor that is complexed with residues from both the receptor and peptide ligand. Extracellular Ca2+ increases the affinity and potency of the endogenous agonist a-melanocyte–stimulating hormone at the MC4R by 37- and 600-fold, respectively. The ability of the MC4R crystallized construct to couple to ion channel Kir7.1, while lacking cyclic adenosine monophosphate stimulation, highlights a heterotrimeric GTP-binding protein (G protein)–independent mechanism for this signaling modality. MC4R is revealed as a structurally divergent G protein–coupled receptor (GPCR), with more similarity to lipidic GPCRs than to the homologous peptidic GPCRs. © 2020 American Association for the Advancement of Science. All rights reserved.
关键词	alpha intermedin calcium ion cyclic AMP G protein coupled receptor heterotrimeric guanine nucleotide binding protein inwardly rectifying potassium channel inwardly rectifying potassium channel subunit Kir7.1 melanocortin 4 receptor n acetyl alpha intermedin[4-10]cyclo[4 norleucine 5 aspartic acid 7 [3 (2 naphthyl)alanine] 10 lysinamide]unclassified drug calcium G protein coupled receptor intermedin inwardly rectifying potassium channel Kir7.1 channel ligand melanocortin 4 receptor n acetyl alpha intermedin[4-10]cyclo[4 norleucine 5 aspartic acid 7 [3 (2 naphthyl)alanine] 10 lysinamide]protein binding calcium chemical binding homeostasis hormone ligand obesity peptide protein Article binding affinity complex formation crystallization drug structure extracellular calcium human ligand binding priority journal protein structure receptor blocking signal transduction chemistry genetics mutation protein multimerization protein secondary structure X ray crystallography Calcium Crystallography, X-Ray Cyclic AMP Humans Ligands Melanocyte-Stimulating Hormones Mutation Potassium Channels, Inwardly Rectifying Protein Binding Protein Multimerization Protein Structure, Secondary Receptor, Melanocortin, Type 4 Receptors, G-Protein-Coupled Signal Transduction
语种	英语
来源机构	Science
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/133545
推荐引用方式 GB/T 7714	Yu J.,Gimenez L.E.,Hernandez C.C.,et al. Determination of the melanocortin-4 receptor structure identifies Ca2+ as a cofactor for ligand binding[J]. Science,2020,368(6489).
APA	Yu J..,Gimenez L.E..,Hernandez C.C..,Wu Y..,Wein A.H..,...&Stevens R.C..(2020).Determination of the melanocortin-4 receptor structure identifies Ca2+ as a cofactor for ligand binding.,368(6489).
MLA	Yu J.,et al."Determination of the melanocortin-4 receptor structure identifies Ca2+ as a cofactor for ligand binding".368.6489(2020).