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

Zhang, Xianjun; Zhao, Fei; Wu, Yiran; Yang, Jun; Han, Gye Won; Zhao, Suwen; Ishchenko, Andrii; Ye, Lintao; Lin, Xi; Ding, Kang; Dharmarajan, Venkatasubramanian; Griffin, Patrick R.; Gati, Cornelius; Nelson, Garrett; Hunter, Mark S.; Hanson, Michael A.; Cherezov, Vadim; Stevens, Raymond C.; Tan, Wenfu; Tao, Houchao; Xu, Fei

doi:10.1038/ncomms15383

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

Journal Article · Wed May 17 00:00:00 EDT 2017 · Nature Communications

DOI:https://doi.org/10.1038/ncomms15383· OSTI ID:1368693

Zhang, Xianjun ^[1]; Zhao, Fei ^[2]; Wu, Yiran ^[2]; Yang, Jun ^[3]; Han, Gye Won ^[4]; Zhao, Suwen ^[2]; Ishchenko, Andrii ^[4]; Ye, Lintao ^[5]; Lin, Xi ^[1];

^[5]; Dharmarajan, Venkatasubramanian ^[6]; Griffin, Patrick R. ^[6]; Gati, Cornelius ^[7]; Nelson, Garrett ^[8]; Hunter, Mark S. ^[9]; Hanson, Michael A. ^[10];

^[4]; Stevens, Raymond C. ^[2]; Tan, Wenfu ^[3]; Tao, Houchao ^[2] more »

ShanghaiTech Univ., Shanghai (China); Chinese Academy of Sciences, Shanghai (China); Univ. of Chinese Academy of Sciences, Beijing (China)
ShanghaiTech Univ., Shanghai (China)
Fudan Univ., Shanghai (China)
Univ. of Southern California, Los Angeles, CA (United States)
ShanghaiTech Univ., Shanghai (China); Univ. of Chinese Academy of Sciences, Shanghai (China)
The Scripps Research Inst., Jupiter, FL (United States)
Lab. of Molecular Biology, Cambridge (United Kingdom)
Arizona State Univ., Tempe, AZ (United States)
SLAC National Accelerator Lab., Menlo Park, CA (United States)
GPCR Consortium, San Marcos, CA (United States)

Here, 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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Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1368693

Journal Information:: Nature Communications, Vol. 8; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 69 works

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