Converse conformational control of smoothened activity by structurally related small molecules

Hongbo Yang, Jing Xiang, Nengdong Wang, Yun Zhao, Joel Hyman, Song Li, Jin Jiang, James K. Chen, Zhen Yang*, Shuo Lin

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

44 Scopus citations


The seven-pass transmembrane protein Smoothened (Smo) is an essential component of the Hedgehog (Hh) signaling pathway that is critically involved in normal animal development as well as pathological malignancies. In studying Hh-related biological processes, it would be highly desirable if Smo activity could be instantly switched between activation and inhibition. Using Gli1-dependent GFP transgenic zebrafish and in vitro biochemical assays, we identified and characterized two potent Smo inhibitors, SANT74 and 75 (Smoothened antagonist 74 and 75), by screening a small molecule library designed based on the scaffold of Smo agonist SAG. These compounds are structural analogs of SAG with the methyl group substituted by a propyl or allyl group in SANTs. We show that SANTs and SAG exert opposite effects on Smo activity by regulating protein conformation. Our study represents the first demonstration of conformational regulation of Smo by small molecule analogs, and the combinational use of these Smo modulators in a temporal controlled fashion should be useful for studying Hh biology.

Original languageEnglish (US)
Pages (from-to)20876-20884
Number of pages9
JournalJournal of Biological Chemistry
Issue number31
StatePublished - Jul 31 2009
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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