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

Xiaofeng Qi, Heng Liu, Bonne Thompson, Jeffrey McDonald, Cheng Zhang, Xiaochun Li

Research output: Contribution to journalArticlepeer-review

87 Scopus citations


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 pathway1,2. 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 proteins3. 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.

Original languageEnglish (US)
Pages (from-to)279-283
Number of pages5
Issue number7764
StatePublished - Jul 11 2019

ASJC Scopus subject areas

  • General


Dive into the research topics of 'Cryo-EM structure of oxysterol-bound human Smoothened coupled to a heterotrimeric Gi'. Together they form a unique fingerprint.

Cite this