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Nat Commun. 2017 May 17;8:15383. doi: 10.1038/ncomms15383.

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

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iHuman Institute, ShanghaiTech University, 2F Building 6, 99 Haike Road, Pudong New District, Shanghai 201210, China.
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China.
Departments of Chemistry, Biological Sciences and Physics &Astronomy, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA.
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 555 Zuchongzhi Lu, Building 3, Room 426, Shanghai 201203, China.
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, Shanghai 200031, China.
Department of Molecular Therapeutics, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, USA.
Medical Research Council, Laboratory of Molecular Biology, Cambridge, Biomedical Campus, Francis Crick Avenue, Cambridge CB2 OQH, UK.
Department of Physics, Arizona State University, Tempe, Arizona 85287, USA.
Linac Coherent Light Source, SLAC National Accelerator Laboratory, 2575 Sand Hill Road, Menlo Park, California 94025, USA.
GPCR Consortium, San Marcos, California 92078, USA.


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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