skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

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

Abstract

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.

Authors:
 [1];  [2];  [2];  [3];  [4];  [2];  [4];  [5];  [1]; ORCiD logo [5];  [6];  [6];  [7];  [8];  [9];  [10]; ORCiD logo [4];  [2];  [3];  [2] more »;  [2] « less
  1. ShanghaiTech Univ., Shanghai (China); Chinese Academy of Sciences, Shanghai (China); Univ. of Chinese Academy of Sciences, Beijing (China)
  2. ShanghaiTech Univ., Shanghai (China)
  3. Fudan Univ., Shanghai (China)
  4. Univ. of Southern California, Los Angeles, CA (United States)
  5. ShanghaiTech Univ., Shanghai (China); Univ. of Chinese Academy of Sciences, Shanghai (China)
  6. The Scripps Research Inst., Jupiter, FL (United States)
  7. Lab. of Molecular Biology, Cambridge (United Kingdom)
  8. Arizona State Univ., Tempe, AZ (United States)
  9. SLAC National Accelerator Lab., Menlo Park, CA (United States)
  10. GPCR Consortium, San Marcos, CA (United States)
Publication Date:
Research Org.:
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1368693
Grant/Contract Number:
AC02-76SF00515
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 8; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; 59 BASIC BIOLOGICAL SCIENCES; developmental biology; nanocrystallography

Citation Formats

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, and Xu, Fei. Crystal structure of a multi-domain human smoothened receptor in complex with a super stabilizing ligand. United States: N. p., 2017. Web. doi:10.1038/ncomms15383.
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. Crystal structure of a multi-domain human smoothened receptor in complex with a super stabilizing ligand. United States. doi:10.1038/ncomms15383.
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, and Xu, Fei. 2017. "Crystal structure of a multi-domain human smoothened receptor in complex with a super stabilizing ligand". United States. doi:10.1038/ncomms15383. https://www.osti.gov/servlets/purl/1368693.
@article{osti_1368693,
title = {Crystal structure of a multi-domain human smoothened receptor in complex with a super stabilizing ligand},
author = {Zhang, Xianjun and Zhao, Fei and Wu, Yiran and Yang, Jun and Han, Gye Won and Zhao, Suwen and Ishchenko, Andrii and Ye, Lintao and Lin, Xi and Ding, Kang and Dharmarajan, Venkatasubramanian and Griffin, Patrick R. and Gati, Cornelius and Nelson, Garrett and Hunter, Mark S. and Hanson, Michael A. and Cherezov, Vadim and Stevens, Raymond C. and Tan, Wenfu and Tao, Houchao and Xu, Fei},
abstractNote = {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.},
doi = {10.1038/ncomms15383},
journal = {Nature Communications},
number = ,
volume = 8,
place = {United States},
year = 2017,
month = 5
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 1work
Citation information provided by
Web of Science

Save / Share: