Journal
NATURE COMMUNICATIONS
Volume 8, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms15383
Keywords
-
Categories
Funding
- Science and Technology Commission of Shanghai Municipality [14PJ1406700]
- National '1000 Talents' young scientist grant
- National Institutes of Health (NIH) [R01 GM108635]
- National Science Foundation (NSF) [1231306]
- Human Frontier Science Program [LT000087/2015-L]
- NIH [P41GM103393]
- Shanghai Municipal Government, ShanghaiTech University
- US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]
- Mammalian Expression Core Facility of iHuman Institute
- Medical Research Council [MC_UP_A025_1013] Funding Source: researchfish
- MRC [MC_UP_A025_1013] Funding Source: UKRI
Ask authors/readers for more resources
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 angstrom. 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
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available