| Title | Converse Conformational Control of Smoothened Activity by Structurally Related Small Molecules |
| Authors | Yang, Hongbo Xiang, Jing Wang, Nengdong Zhao, Yun Hyman, Joel Li, Song Jiang, Jin Chen, James K. Yang, Zhen Lin, Shuo |
| Affiliation | Peking Univ, Shenzhen Grad Sch, Lab Chem Genom, Shenzhen 518055, Peoples R China. Peking Univ, Coll Life Sci, Beijing 100871, Peoples R China. Peking Univ, Coll Chem & Mol Engn, Beijing 100871, Peoples R China. Univ Texas SW Med Ctr Dallas, Dept Dev Biol, Dallas, TX 75390 USA. Chinese Acad Sci, Inst Biochem & Cell Biol, Shanghai 200031, Peoples R China. Stanford Univ, Sch Med, Dept Chem & Syst Biol, Stanford, CA 94305 USA. Shenzhen Shengjie Biotech Co Ltd, Shenzhen 518055, Peoples R China. Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 USA. |
| Keywords | HEDGEHOG SIGNALING PATHWAY BASAL-CELL CARCINOMA SONIC HEDGEHOG HUMAN HOMOLOG BRAIN-TUMORS FLOOR PLATE MEDULLOBLASTOMA INHIBITION PROLIFERATION CYCLOPAMINE |
| Issue Date | 2009 |
| Publisher | journal of biological chemistry |
| Citation | JOURNAL OF BIOLOGICAL CHEMISTRY.2009,284,(31),20876-20884. |
| Abstract | 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. |
| URI | http://hdl.handle.net/20.500.11897/320004 |
| ISSN | 0021-9258 |
| DOI | 10.1074/jbc.M807648200 |
| Indexed | SCI(E) EI PubMed |
| Appears in Collections: | 深圳研究生院待认领 生命科学学院 å å¦ä¸ å å å·¥ç¨ å¦é ¢ |
