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Chen JK, Taipale J, Cooper MK, Beachy PA.
Inhibition of Hedgehog signaling by direct
binding of cyclopamine to Smoothened.
Genes Dev. 2002 Nov 1;16(21):2743-8 Department of
Molecular Biology and Genetics, Howard
Hughes Medical Institute, Johns Hopkins
University School of Medicine,
Baltimore, Maryland 21205, USA.
The steroidal
alkaloid cyclopamine has both
teratogenic and antitumor activities
arising from its ability to specifically
block cellular responses to vertebrate
Hedgehog signaling. We show here, using
photoaffinity and fluorescent
derivatives, that this inhibitory effect
is mediated by direct binding of
cyclopamine to the heptahelical bundle
of Smoothened (Smo). Cyclopamine also
can reverse the retention of partially
misfolded Smo in the endoplasmic
reticulum, presumably through
binding-mediated effects on protein
conformation. These observations reveal
the mechanism of cyclopamine's
teratogenic and antitumor activities and
further suggest a role for small
molecules in the physiological
regulation of Smo.
PMID: 12414725
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