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

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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  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:
Grant/Contract Number:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 8; Journal ID: ISSN 2041-1723
Nature Publishing Group
Research Org:
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org:
Country of Publication:
United States
36 MATERIALS SCIENCE; 59 BASIC BIOLOGICAL SCIENCES; developmental biology; nanocrystallography
OSTI Identifier: