Crystal structure of a multi-domain human smoothened receptor in complex with a super stabilizing ligand
文献类型：期刊论文
| 作者 | Zhang, Xianjun3,4,5,6; Zhao, Fei4; Wu, Yiran4; Yang, Jun; Han, Gye Won7,8,9; Zhao, Suwen5; Ishchenko, Andrii; Ye, Lintao5,10; Lin, Xi3,5,6; Ding, Kang5,11 |
| 刊名 | NATURE COMMUNICATIONS
 |
| 出版日期 | 2017-05-17 |
| 卷号 | 8 |
| ISSN号 | 2041-1723 |
| DOI | 10.1038/ncomms15383 |
| 文献子类 | Article |
| 英文摘要 | 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. |
| WOS关键词 | SERIAL FEMTOSECOND CRYSTALLOGRAPHY ; BASAL-CELL CARCINOMA ; LIPIDIC CUBIC PHASE ; MEMBRANE-PROTEINS ; FORCE-FIELD ; HEDGEHOG ; MODULATION ; MESOPHASES ; SOFTWARE ; AMBER |
| 资助项目 | Science and Technology Commission of Shanghai Municipality[14PJ1406700] ; National '1000 Talents' young scientist grant[00000000] ; National Institutes of Health (NIH)[R01 GM108635] ; National Science Foundation (NSF)[1231306] ; Human Frontier Science Program[LT000087/2015-L] ; NIH[P41GM103393] ; Shanghai Municipal Government, ShanghaiTech University[00000000] ; US Department of Energy, Office of Science, Office of Basic Energy Sciences[DE-AC02-76SF00515] ; Mammalian Expression Core Facility of iHuman Institute[00000000] |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| WOS记录号 | WOS:000401512300001 |
| 出版者 | NATURE PUBLISHING GROUP |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/272661]  |
| 专题 | 药理学第一研究室 |
| 通讯作者 | Tan, Wenfu; Tao, Houchao; Xu, Fei |
| 作者单位 | 1.Arizona State Univ, Dept Phys, Tempe, AZ 85287 USA; 2.Fudan Univ, Sch Pharm, Dept Pharmacol, Shanghai 201203, Peoples R China; 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China; 4.ShanghaiTech Univ, IHuman Inst, 2F Bldg 6,99 Haike Rd, Shanghai 201210, Peoples R China; 5.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China; 6.Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Shanghai 200031, Peoples R China; 7.Univ Southern Calif, Dept Chem, Los Angeles, CA 90089 USA; 8.Univ Southern Calif, Dept Biol Sci, Los Angeles, CA 90089 USA; 9.Univ Southern Calif, Dept Phys & Astron, Los Angeles, CA 90089 USA; 10.Chinese Acad Sci, Shanghai Inst Mat Medica, Univ Chinese Acad Sci, 555 Zuchongzhi Lu, Bldg 3,Room 426, Shanghai 201203, Peoples R China; |
| 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. |
| 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. |
| MLA | Zhang, Xianjun,et al."Crystal structure of a multi-domain human smoothened receptor in complex with a super stabilizing ligand".NATURE COMMUNICATIONS 8(2017). |
入库方式： OAI收割
来源：上海药物研究所
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