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 Won6,7,8; Zhao, Suwen2; Ishchenko, Andrii; Ye, Lintao2,9; Lin, Xi2,3,4; Ding, Kang2,10; Dharmarajan, Venkatasubramanian11; Griffin, Patrick R.; Gati, Cornelius12; Nelson, Garrett13; Hunter, Mark S.14; Hanson, Michael A.15; Cherezov, Vadim6,7,8; Stevens, Raymond C.; Tan, Wenfu1,5; Tao, Houchao1; Xu, Fei1,2
2017-05-17
Source PublicationNATURE COMMUNICATIONS
ISSN2041-1723
Volume8Issue:1
Status已发表
DOI10.1038/ncomms15383
Abstract

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.

Indexed BySCI
Language英语
Funding ProjectUS Department of Energy, Office of Science, Office of Basic Energy Sciences[DE-AC02-76SF00515]
WOS Research AreaScience & Technology - Other Topics
WOS SubjectMultidisciplinary Sciences
WOS IDWOS:000401512300001
PublisherNATURE PUBLISHING GROUP
WOS KeywordSERIAL FEMTOSECOND CRYSTALLOGRAPHY ; BASAL-CELL CARCINOMA ; LIPIDIC CUBIC PHASE ; MEMBRANE-PROTEINS ; FORCE-FIELD ; HEDGEHOG ; MODULATION ; MESOPHASES ; SOFTWARE ; AMBER
Original Document TypeArticle
Citation statistics
Cited Times:56[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttps://kms.shanghaitech.edu.cn/handle/2MSLDSTB/1364
CollectioniHuman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
Corresponding AuthorTan, Wenfu; Tao, Houchao; Xu, Fei
Affiliation1.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
First Author AffilicationiHuman Institute;  School of Life Science and Technology
Corresponding Author AffilicationiHuman Institute;  School of Life Science and Technology
First Signature AffilicationiHuman Institute
Recommended Citation
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).
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