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-Structure paper
Title | Cryo-EM structure of oxysterol-bound human Smoothened coupled to a heterotrimeric G. |
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Journal, issue, pages | Nature, Vol. 571, Issue 7764, Page 279-283, Year 2019 |
Publish date | Jun 5, 2019 |
Authors | Xiaofeng Qi / Heng Liu / Bonne Thompson / Jeffrey McDonald / Cheng Zhang / Xiaochun Li / |
PubMed Abstract | The oncoprotein Smoothened (SMO), a G-protein-coupled receptor (GPCR) of the Frizzled-class (class-F), transduces the Hedgehog signal from the tumour suppressor Patched-1 (PTCH1) to the glioma- ...The oncoprotein Smoothened (SMO), a G-protein-coupled receptor (GPCR) of the Frizzled-class (class-F), transduces the Hedgehog signal from the tumour suppressor Patched-1 (PTCH1) to the glioma-associated-oncogene (GLI) transcription factors, which activates the Hedgehog signalling pathway. It has remained unknown how PTCH1 modulates SMO, how SMO is stimulated to form a complex with heterotrimeric G proteins and whether G-protein coupling contributes to the activation of GLI proteins. Here we show that 24,25-epoxycholesterol, which we identify as an endogenous ligand of PTCH1, can stimulate Hedgehog signalling in cells and can trigger G-protein signalling via human SMO in vitro. We present a cryo-electron microscopy structure of human SMO bound to 24(S),25-epoxycholesterol and coupled to a heterotrimeric G protein. The structure reveals a ligand-binding site for 24(S),25-epoxycholesterol in the 7-transmembrane region, as well as a G-coupled activation mechanism of human SMO. Notably, the G protein presents a different arrangement from that of class-A GPCR-G complexes. Our work provides molecular insights into Hedgehog signal transduction and the activation of a class-F GPCR. |
External links | Nature / PubMed:31168089 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.84 Å |
Structure data | EMDB-20190, PDB-6ot0: |
Chemicals | ChemComp-CO1: |
Source |
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Keywords | SIGNALING PROTEIN / GPCR / Complex / Hedgehog signaling |