IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v8y2017i1d10.1038_ncomms15383.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/ncomms15383
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/ncomms15383?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    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.
    2. Julien Bous & Julia Kinsolving & Lukas Grätz & Magdalena M. Scharf & Jan Hendrik Voss & Berkay Selcuk & Ogün Adebali & Gunnar Schulte, 2024. "Structural basis of frizzled 7 activation and allosteric regulation," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15383. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.