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论文题目: Crystal structure of a multi-domain human smoothened receptor in complex with a super stabilizing ligand
英文论文题目: Crystal structure of a multi-domain human smoothened receptor in complex with a super stabilizing ligand
第一作者: Zhang, XJ; Zhao, F; Wu, YR; Yang, J; Han, GW; Zhao, SW; Ishchenko, A; Ye, LT; Lin, X; Ding, K; Dharmarajan, V; Griffin, PR; Gati, C; Nelson, G; Hunter, MS; Hanson, MA; Cherezov, V; Stevens, RC; Tan, WF; Tao, HC; Xu, F
英文第一作者: Zhang, XJ; Zhao, F; Wu, YR; Yang, J; Han, GW; Zhao, SW; Ishchenko, A; Ye, LT; Lin, X; Ding, K; Dharmarajan, V; Griffin, PR; Gati, C; Nelson, G; Hunter, MS; Hanson, MA; Cherezov, V; Stevens, RC; Tan, WF; Tao, HC; Xu, F
联系作者: Tao, HC; Xu, F (reprint author), ShanghaiTech Univ, IHuman Inst, 2F Bldg 6,99 Haike Rd, Shanghai 201210, Peoples R China.
英文联系作者: Tao, HC; Xu, F (reprint author), ShanghaiTech Univ, IHuman Inst, 2F Bldg 6,99 Haike Rd, Shanghai 201210, Peoples R China.
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发表年度: 2017
卷: 8
期:
页码: 15383
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.
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.
刊物名称: NATURE COMMUNICATIONS
英文刊物名称: NATURE COMMUNICATIONS
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学科: Multidisciplinary Sciences
英文学科: Multidisciplinary Sciences
影响因子: 12.124
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论文类别: Article
英文论文类别: Article
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