Climate Change Data Portal
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 intermedincalcium ioncyclic AMPG protein coupled receptorheterotrimeric guanine nucleotide binding proteininwardly rectifying potassium channelinwardly rectifying potassium channel subunit Kir7.1melanocortin 4 receptorn acetyl alpha intermedin[4-10]cyclo[4 norleucine 5 aspartic acid 7 [3 (2 naphthyl)alanine] 10 lysinamide]unclassified drugcalciumG protein coupled receptorintermedininwardly rectifying potassium channelKir7.1 channelligandmelanocortin 4 receptorn acetyl alpha intermedin[4-10]cyclo[4 norleucine 5 aspartic acid 7 [3 (2 naphthyl)alanine] 10 lysinamide]protein bindingcalciumchemical bindinghomeostasishormoneligandobesitypeptideproteinArticlebinding affinitycomplex formationcrystallizationdrug structureextracellular calciumhumanligand bindingpriority journalprotein structurereceptor blockingsignal transductionchemistrygeneticsmutationprotein multimerizationprotein secondary structureX ray crystallographyCalciumCrystallography, X-RayCyclic AMPHumansLigandsMelanocyte-Stimulating HormonesMutationPotassium Channels, Inwardly RectifyingProtein BindingProtein MultimerizationProtein Structure, SecondaryReceptor, Melanocortin, Type 4Receptors, G-Protein-CoupledSignal 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). |
条目包含的文件 | 条目无相关文件。 |
除非特别说明,本系统中所有内容都受版权保护,并保留所有权利。