Crystal structure of a multi-domain human smoothened receptor in complex with a super stabilizing ligand

doi:10.1038/ncomms15383

KMS > iHuman研究所

	Crystal structure of a multi-domain human smoothened receptor in complex with a super stabilizing ligand
	Zhang, Xianjun1,2,3,4 ; Zhao, Fei1 ; Wu, Yiran1 ; Yang, Jun ; Han, Gye Won 6,7,8; Zhao, Suwen2 ; Ishchenko, Andrii ; Ye, Lintao2,9 ; Lin, Xi2,3,4 ; Ding, Kang2,10 ; Dharmarajan, Venkatasubramanian 11; Griffin, Patrick R.; Gati, Cornelius 12; Nelson, Garrett 13; Hunter, Mark S.14; Hanson, Michael A.15; Cherezov, Vadim 6,7,8; Stevens, Raymond C.; Tan, Wenfu 1,5; Tao, Houchao1 ; Xu, Fei1,2
	2017-05-17
发表期刊	NATURE COMMUNICATIONS
ISSN	2041-1723
卷号	8 期号:1
发表状态	已发表
DOI	10.1038/ncomms15383
摘要	The Smoothened receptor (SMO) belongs to the Class Frizzled of the G protein-coupled receptor (GPCR) superfamily, constituting a key component of the Hedgehog signalling pathway. Here we report the crystal structure of the multi-domain human SMO, bound and stabilized by a designed tool ligand TC114, using an X-ray free-electron laser source at 2.9 angstrom. The structure reveals a precise arrangement of three distinct domains: a seven-transmembrane helices domain (TMD), a hinge domain (HD) and an intact extracellular cysteine-rich domain (CRD). This architecture enables allosteric interactions between the domains that are important for ligand recognition and receptor activation. By combining the structural data, molecular dynamics simulation, and hydrogen-deuterium-exchange analysis, we demonstrate that transmembrane helix VI, extracellular loop 3 and the HD play a central role in transmitting the signal employing a unique GPCR activation mechanism, distinct from other multi-domain GPCRs.
收录类别	SCI
语种	英语
资助项目	US Department of Energy, Office of Science, Office of Basic Energy Sciences[DE-AC02-76SF00515]
WOS研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:000401512300001
出版者	NATURE PUBLISHING GROUP
WOS关键词	SERIAL FEMTOSECOND CRYSTALLOGRAPHY ; BASAL-CELL CARCINOMA ; LIPIDIC CUBIC PHASE ; MEMBRANE-PROTEINS ; FORCE-FIELD ; HEDGEHOG ; MODULATION ; MESOPHASES ; SOFTWARE ; AMBER
原始文献类型	Article
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/1364
专题	iHuman研究所生命科学与技术学院 iHuman研究所_特聘教授组_Andrej Sali组 iHuman研究所_特聘教授组_Raymond Stevens组 iHuman研究所_PI研究组_徐菲组 iHuman研究所_PI研究组_陶厚朝组 iHuman研究所_PI研究组_赵素文组生命科学与技术学院_硕士生生命科学与技术学院_博士生
通讯作者	Tan, Wenfu; Tao, Houchao; Xu, Fei
作者单位	1.ShanghaiTech Univ, IHuman Inst, 2F Bldg 6,99 Haike Rd, Shanghai 201210, Peoples R China 2.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Shanghai 200031, Peoples R China 4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 5.Fudan Univ, Sch Pharm, Dept Pharmacol, Shanghai 201203, Peoples R China 6.Univ Southern Calif, Dept Chem, Los Angeles, CA 90089 USA 7.Univ Southern Calif, Dept Biol Sci, Los Angeles, CA 90089 USA 8.Univ Southern Calif, Dept Phys & Astron, Los Angeles, CA 90089 USA 9.Chinese Acad Sci, Shanghai Inst Mat Medica, Univ Chinese Acad Sci, 555 Zuchongzhi Lu, Bldg 3,Room 426, Shanghai 201203, Peoples R China 10.Chinese Acad Sci, Shanghai Inst Biol Sci, Univ Chinese Acad Sci, CAS MPG Partner Inst Computat Biol, Shanghai 200031, Peoples R China 11.Scripps Res Inst, Dept Mol Therapeut, 130 Scripps Way, Jupiter, FL 33458 USA 12.MRC, Mol Biol Lab, Biomedical Campus,Francis Crick Ave, Cambridge 33458, England 13.MRC, Mol Biol Lab, Biomedical Campus,Francis Crick Ave, Cambridge, England 14.Arizona State Univ, Dept Phys, Tempe, AZ 85287 USA 15.SLAC Natl Accelerator Lab, Linac Coherent Light Source, 2575 Sand Hill Rd, Menlo Pk, CA 94025 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	Zhang, Xianjun,Zhao, Fei,Wu, Yiran,et al. Crystal structure of a multi-domain human smoothened receptor in complex with a super stabilizing ligand[J]. NATURE COMMUNICATIONS,2017,8(1).
APA	Zhang, Xianjun.,Zhao, Fei.,Wu, Yiran.,Yang, Jun.,Han, Gye Won.,...&Xu, Fei.(2017).Crystal structure of a multi-domain human smoothened receptor in complex with a super stabilizing ligand.NATURE COMMUNICATIONS,8(1).
MLA	Zhang, Xianjun,et al."Crystal structure of a multi-domain human smoothened receptor in complex with a super stabilizing ligand".NATURE COMMUNICATIONS 8.1(2017).