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

Author

Listed:
  • Xianjun Zhang

    (iHuman Institute, ShanghaiTech University
    School of Life Science and Technology, ShanghaiTech University
    Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Fei Zhao

    (iHuman Institute, ShanghaiTech University)

  • Yiran Wu

    (iHuman Institute, ShanghaiTech University)

  • Jun Yang

    (School of Pharmacy, Fudan University)

  • Gye Won Han

    (Biological Sciences and Physics & Astronomy, Bridge Institute, University of Southern California)

  • Suwen Zhao

    (iHuman Institute, ShanghaiTech University
    School of Life Science and Technology, ShanghaiTech University)

  • Andrii Ishchenko

    (Biological Sciences and Physics & Astronomy, Bridge Institute, University of Southern California)

  • Lintao Ye

    (iHuman Institute, ShanghaiTech University
    School of Life Science and Technology, ShanghaiTech University
    Shanghai Institute of Materia Medica, Chinese Academy of Sciences, University of Chinese Academy of Sciences)

  • Xi Lin

    (iHuman Institute, ShanghaiTech University
    School of Life Science and Technology, ShanghaiTech University
    Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Kang Ding

    (iHuman Institute, ShanghaiTech University
    School of Life Science and Technology, ShanghaiTech University
    Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences)

  • Venkatasubramanian Dharmarajan

    (The Scripps Research Institute)

  • Patrick R. Griffin

    (The Scripps Research Institute)

  • Cornelius Gati

    (Medical Research Council, Laboratory of Molecular Biology)

  • Garrett Nelson

    (Arizona State University)

  • Mark S. Hunter

    (Linac Coherent Light Source, SLAC National Accelerator Laboratory)

  • Michael A. Hanson

    (GPCR Consortium)

  • Vadim Cherezov

    (Biological Sciences and Physics & Astronomy, Bridge Institute, University of Southern California)

  • Raymond C. Stevens

    (iHuman Institute, ShanghaiTech University
    School of Life Science and Technology, ShanghaiTech University)

  • Wenfu Tan

    (School of Pharmacy, Fudan University)

  • Houchao Tao

    (iHuman Institute, ShanghaiTech University)

  • Fei Xu

    (iHuman Institute, ShanghaiTech University
    School of Life Science and Technology, ShanghaiTech University)

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 Å. 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.

Suggested Citation

  • Xianjun Zhang & Fei Zhao & Yiran Wu & Jun Yang & Gye Won Han & Suwen Zhao & Andrii Ishchenko & Lintao Ye & Xi Lin & Kang Ding & Venkatasubramanian Dharmarajan & Patrick R. Griffin & Cornelius Gati & G, 2017. "Crystal structure of a multi-domain human smoothened receptor in complex with a super stabilizing ligand," Nature Communications, Nature, vol. 8(1), pages 1-10, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15383
    DOI: 10.1038/ncomms15383
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    Cited by:

    1. Kaihua Zhang & Hao Wu & Nicholas Hoppe & Aashish Manglik & Yifan Cheng, 2022. "Fusion protein strategies for cryo-EM study of G protein-coupled receptors," Nature Communications, Nature, vol. 13(1), pages 1-11, December.

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