Cryo-EM structure of oxysterol-bound human Smoothened coupled to a heterotrimeric Gi

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 re...

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Bibliographic Details
Published in:Nature (London) 2019-06, Vol.571 (7764), p.279-283
Main Authors: Qi, Xiaofeng, Liu, Heng, Thompson, Bonne, McDonald, Jeffrey, Zhang, Cheng, Li, Xiaochun
Format: Article
Language:English
Subjects:
Activation
Binding sites
Cholesterol
Coupling (molecular)
Crystal structure
Electron microscopy
Frizzled protein
G protein-coupled receptors
Glioma
Hedgehog protein
Kinases
Ligands
Microscopy
Narcotics
Patched protein
Protein structure
Proteins
Signal transduction
Signaling
Sterols
Transcription factors
Tumors
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Summary: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 Gi protein. The structure reveals a ligand-binding site for 24(S),25-epoxycholesterol in the 7-transmembrane region, as well as a Gi-coupled activation mechanism of human SMO. Notably, the Gi protein presents a different arrangement from that of class-A GPCR-Gi complexes. Our work provides molecular insights into Hedgehog signal transduction and the activation of a class-F GPCR.
ISSN:0028-0836
1476-4687
DOI:10.1038/s41586-019-1286-0