Small molecule modulation of Smoothened activity. Export

@article{citeulike:201617, abstract = {Smoothened (Smo), a distant relative of G protein-coupled receptors, mediates Hedgehog (Hh) signaling during embryonic development and can initiate or transmit ligand-independent pathway activation in tumorigenesis. Although the cellular mechanisms that regulate Smo function remain unclear, the direct inhibition of Smo by cyclopamine, a plant-derived steroidal alkaloid, suggests that endogenous small molecules may be involved. Here we demonstrate that SAG, a chlorobenzothiophene-containing Hh pathway agonist, binds to the Smo heptahelical bundle in a manner that antagonizes cyclopamine action. In addition, we have identified four small molecules that directly inhibit Smo activity but are structurally distinct from cyclopamine. Functional and biochemical studies of these compounds provide evidence for the small molecule modulation of Smo through multiple mechanisms and yield insights into the physiological regulation of Smo activity. The mechanistic differences between the Smo antagonists may be useful in the therapeutic manipulation of Hh signaling.}, address = {Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.}, author = {Chen, J. K. and Taipale, J. and Young, K. E. and Maiti, T. and Beachy, P. A.}, citeulike-article-id = {201617}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.182542899}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/12391318}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=12391318}, day = {29}, doi = {10.1073/pnas.182542899}, issn = {0027-8424}, journal = {Proc Natl Acad Sci U S A}, keywords = {cyclopamine, hedgehog, smo}, month = {October}, number = {22}, pages = {14071--14076}, posted-at = {2005-05-16 19:23:10}, priority = {2}, title = {Small molecule modulation of Smoothened activity.}, url = {http://dx.doi.org/10.1073/pnas.182542899}, volume = {99}, year = {2002} }

TY - JOUR ID - citeulike:201617 L3 - citeulike-article-id:201617 N2 - Smoothened (Smo), a distant relative of G protein-coupled receptors, mediates Hedgehog (Hh) signaling during embryonic development and can initiate or transmit ligand-independent pathway activation in tumorigenesis. Although the cellular mechanisms that regulate Smo function remain unclear, the direct inhibition of Smo by cyclopamine, a plant-derived steroidal alkaloid, suggests that endogenous small molecules may be involved. Here we demonstrate that SAG, a chlorobenzothiophene-containing Hh pathway agonist, binds to the Smo heptahelical bundle in a manner that antagonizes cyclopamine action. In addition, we have identified four small molecules that directly inhibit Smo activity but are structurally distinct from cyclopamine. Functional and biochemical studies of these compounds provide evidence for the small molecule modulation of Smo through multiple mechanisms and yield insights into the physiological regulation of Smo activity. The mechanistic differences between the Smo antagonists may be useful in the therapeutic manipulation of Hh signaling. IS - 22 JF - Proc Natl Acad Sci U S A SN - 0027-8424 AD - Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. EP - 14076 TI - Small molecule modulation of Smoothened activity. VL - 99 SP - 14071 KW - cyclopamine KW - hedgehog KW - smo AU - Chen, JK AU - Taipale, J AU - Young, KE AU - Maiti, T AU - Beachy, PA PY - 2002/10/29/ UR - http://dx.doi.org/10.1073/pnas.182542899 ER -