6OT0

Structure of human Smoothened-Gi complex

Summary for 6OT0

• Entry DOI: 10.2210/pdb6ot0/pdb
• EMDB information: 20190
• Descriptor: Smoothened homolog, Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (7 entities in total)
• Functional Keywords: gpcr, complex, hedgehog signaling, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 198577.19

Authors

Qi, X.,Li, X. (deposition date: 2019-05-02, release date: 2019-06-12, Last modification date: 2024-11-13)

Primary citation

Qi, X.,Liu, H.,Thompson, B.,McDonald, J.,Zhang, C.,Li, X.
Cryo-EM structure of oxysterol-bound human Smoothened coupled to a heterotrimeric Gi.
Nature, 571:279-283, 2019

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-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.

PubMed: 31168089
DOI: 10.1038/s41586-019-1286-0

Experimental method

ELECTRON MICROSCOPY (3.84 Å)