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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- Crystal Structure of a Multi-Domain Human Smoothened Receptor in Complex With a Super Stabilizing Ligand
- Zhang, Xianjun (Author)
- Zhao, Fei (Author)
- Wu, Yiran (Author)
- Yang, Jun (Author)
- Han, Gye Won (Author)
- Zhao, Suwen (Author)
- Ishchenko, Andrii (Author)
- Ye, Lintao (Author)
- Lin, Xi (Author)
- Ding, Kang (Author)
- Dharmarajan, Venkatasubramaniam (Author)
- Griffin, Patrick R. (Author)
- Gati, Cornelius (Author)
- Nelson, Garrett (Author)
- Hunter, Mark S. (Author)
- Hanson, Michael A. (Author)
- Cherezov, Vadim (Author)
- Stevens, Raymond C. (Author)
- Tan, Wenfu (Author)
- Tao, Houchao (Author)
- Xu, Fei (Author)
- College of Liberal Arts and Sciences (Contributor)
- Digital object identifier: 10.1038/ncomms15383
- Identifier TypeInternational standard serial numberIdentifier Value2041-1723
- 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