Sterols in an intramolecular channel of Smoothened mediate Hedgehog signaling

Xiaofeng Qi, Lucas Friedberg, Ryan De Bose-Boyd, Tao Long, Xiaochun Li

Research output: Contribution to journalArticlepeer-review

46 Scopus citations


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, SMOD384R and SMOG111C/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. [Figure not available: see fulltext.]

Original languageEnglish (US)
Pages (from-to)1368-1375
Number of pages8
JournalNature chemical biology
Issue number12
StatePublished - Dec 2020

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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