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

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, Garrett Nelson, Mark S. Hunter, Michael A. Hanson, Vadim Cherezov, Raymond C. Stevens, Wenfu Tan (), Houchao Tao () and Fei Xu ()
Additional contact information
Xianjun Zhang: iHuman Institute, ShanghaiTech University
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
Andrii Ishchenko: Biological Sciences and Physics & Astronomy, Bridge Institute, University of Southern California
Lintao Ye: iHuman Institute, ShanghaiTech University
Xi Lin: iHuman Institute, ShanghaiTech University
Kang Ding: iHuman Institute, ShanghaiTech University
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
Wenfu Tan: School of Pharmacy, Fudan University
Houchao Tao: iHuman Institute, ShanghaiTech University
Fei Xu: iHuman Institute, ShanghaiTech University

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15383

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