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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

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.

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    Title
    • Crystal Structure of a Multi-Domain Human Smoothened Receptor in Complex With a Super Stabilizing Ligand
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    Date Created
    2017-05-17
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    Identifier
    • Digital object identifier: 10.1038/ncomms15383
    • Identifier Type
      International standard serial number
      Identifier Value
      2041-1723
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    • The final version of this article, as published in Nature Communications, can be viewed online at: http://www.nature.com/articles/ncomms15383

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    Zhang, X., Zhao, F., Wu, Y., Yang, J., Han, G. W., Zhao, S., . . . Xu, F. (2017). Crystal structure of a multi-domain human smoothened receptor in complex with a super stabilizing ligand. Nature Communications, 8, 15383. doi:10.1038/ncomms15383

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