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Publication Abstract from PubMed

Smoothened (SMO), a class Frizzled G protein-coupled receptor (class F GPCR), transduces the Hedgehog signal across the cell membrane. Sterols can bind to its extracellular cysteine-rich domain (CRD) and to several sites in the seven transmembrane helices (7-TMs) of SMO. However, the mechanism by which sterols regulate SMO via multiple sites is unknown. Here we determined the structures of SMO-Gi complexes bound to the synthetic SMO agonist (SAG) and to 24(S),25-epoxycholesterol (24(S),25-EC). A novel sterol-binding site in the extracellular extension of TM6 was revealed to connect other sites in 7-TMs and CRD, forming an intramolecular sterol channel from the middle side of 7-TMs to CRD. Additional structures of two gain-of-function variants, SMO(D384R) and SMO(G111C/I496C), showed that blocking the channel at its midpoints allows sterols to occupy the binding sites in 7-TMs, thereby activating SMO. These data indicate that sterol transport through the core of SMO is a major regulator of SMO-mediated signaling.

Sterols in an intramolecular channel of Smoothened mediate Hedgehog signaling.,Qi X, Friedberg L, De Bose-Boyd R, Long T, Li X Nat Chem Biol. 2020 Sep 14. pii: 10.1038/s41589-020-0646-2. doi:, 10.1038/s41589-020-0646-2. PMID:32929279^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.