Determination of the melanocortin-4 receptor structure identifies Ca2+ as a cofactor for ligand binding

doi:10.1126/science.aaz8995

	Determination of the melanocortin-4 receptor structure identifies Ca2+ as a cofactor for ligand binding
	Yu, Jing1,2,3 ; Gimenez, Luis E.4; Hernandez, Ciria C.4; Wu, Yiran1 ; Wein, Ariel H.5,6; Han, Gye Won 5,6; McClary, Kyle 5,6; Mittal, Sanraj R.5,6; Burdsall, Kylie 5,6; Stauch, Benjamin 5,6; Wu, Lijie1 ; Stevens, Sophia N.1; Peisley, Alys 4; Williams, Savannah Y.4; Chen, Valerie 7; Millhauser, Glenn L.7; Zhao, Suwen1,2 ; Cone, Roger D.4,8; Stevens, Raymond C.1,2,5,6
	2020-04-24
发表期刊	SCIENCE (IF:44.7[JCR-2023],50.3[5-Year])
ISSN	0036-8075
EISSN	1095-9203
卷号	368 期号:6489 页码:428-+
发表状态	已发表
DOI	10.1126/science.aaz8995
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 alpha-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.
收录类别	SCI ; SCIE
语种	英语
资助项目	EMBO long-term postdoctoral fellowship[ALTF 677-2014]
WOS研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:000528513300046
出版者	AMER ASSOC ADVANCEMENT SCIENCE
WOS关键词	CRYSTAL-STRUCTURE ; MOLECULAR DETERMINANTS ; MC4R ; SIGNATURES ; VARIANTS ; AGONISM ; OBESITY
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/119534
专题	iHuman研究所_PI研究组_赵素文组 iHuman研究所_特聘教授组_Raymond Stevens组 iHuman研究所_科学装置(X)_膜蛋白同步辐射线站生命科学与技术学院_博士生
通讯作者	Cone, Roger D.; Stevens, Raymond C.
作者单位	1.ShanghaiTech Univ, IHuman Inst, Shanghai 201210, Peoples R China 2.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 3.Univ Chinese Acad Sci, CAS Ctr Excellence Mol Cell Sci, Shanghai Inst Biochem & Cell Biol, Chinese Acad Sci, Shanghai 200031, Peoples R China 4.Univ Michigan, Life Sci Inst, Ann Arbor, MI 48109 USA 5.Univ Southern Calif, Dept Biol Sci, Bridge Inst, USC Michelson Ctr Convergent Biosci, Los Angeles, CA 90089 USA 6.Univ Southern Calif, Dept Chem, Bridge Inst, USC Michelson Ctr Convergent Biosci, Los Angeles, CA 90089 USA 7.Univ Calif Santa Cruz, Dept Chem & Biochem, Santa Cruz, CA 95064 USA 8.Univ Michigan, Sch Med, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA
第一作者单位	iHuman研究所; 生命科学与技术学院
通讯作者单位	iHuman研究所; 生命科学与技术学院
第一作者的第一单位	iHuman研究所
推荐引用方式 GB/T 7714	Yu, Jing,Gimenez, Luis E.,Hernandez, Ciria C.,et al. Determination of the melanocortin-4 receptor structure identifies Ca2+ as a cofactor for ligand binding[J]. SCIENCE,2020,368(6489):428-+.
APA	Yu, Jing.,Gimenez, Luis E..,Hernandez, Ciria C..,Wu, Yiran.,Wein, Ariel H..,...&Stevens, Raymond C..(2020).Determination of the melanocortin-4 receptor structure identifies Ca2+ as a cofactor for ligand binding.SCIENCE,368(6489),428-+.
MLA	Yu, Jing,et al."Determination of the melanocortin-4 receptor structure identifies Ca2+ as a cofactor for ligand binding".SCIENCE 368.6489(2020):428-+.