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

Nature Communications
Xianjun ZhangFei Xu

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.

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Methods Mentioned

BETA
X-ray
column chromatography
PCR
transfection
size-exclusion chromatography
single crystal diffraction
Assay
transfections

Software Mentioned

HDX Workbench
CrystFEL
COOT
CHARMM
GraphPad Prism
GUI
XDS
Gromacs
Schrödinger
autoBUSTER

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