TY - JOUR
T1 - Structural characterization of a subtype-selective ligand reveals a novel mode of estrogen receptor antagonism
AU - Shiau, Andrew K.
AU - Barstad, Danielle
AU - Radek, James T.
AU - Meyers, Marvin J.
AU - Nettles, Kendall W.
AU - Katzenellenbogen, Benita S.
AU - Katzenellenbogen, John A.
AU - Agard, David A.
AU - Greene, Geoffrey L.
N1 - Funding Information:
We thank T. Earnest for advice and assistance at beamline 5.0.2 (ALS is funded by the US Department of Energy Office of Basic Energy Sciences). We also thank M. Butte, N. Ota and Y. Shibata for assistance with data collection; P. Coward, A. Derman, and Y. Li for comments on the manuscript; and H. Deacon for extensive graphical assistance. This work was supported by the NIH (B.S.K, J.A.K. and D.A.A), the Howard Hughes Medical Institute (D.A.A.), the Susan G. Komen Breast Cancer Foundation (G.L.G.), the USAMRMC (G.L.G.) and the Illinois Department of Public Health (G.L.G). In the initial phases of this work, A.K.S. was supported by a Howard Hughes Medical Institute Predoctoral Fellowship and a UCSF Chancellor’s Fellowship. All crystallographic studies were completed while A.K.S. was at UCSF, and the peptide binding studies were performed by A.K.S. at Tularik Inc.
PY - 2002
Y1 - 2002
N2 - The R,R enantiomer of 5,11-cis-diethyl-5,6,11,12-tetrahydrochrysene-2,8-diol (THC) exerts opposite effects on the transcriptional activity of the two estrogen receptor (ER) subtypes, ERα and ERβ. THC acts as an ERα agonist and as an ERβ antagonist. We have determined the crystal structures of the ERα ligand binding domain (LBD) bound to both THC and a fragment of the transcriptional coactivator GRIP1, and the ERβ LBD bound to THC. THC stabilizes a conformation of the ERα LBD that permits coactivator association and a conformation of the ERβ LBD that prevents coactivator association. A comparison of the two structures, taken together with functional data, reveals that THC does not act on ERβ through the same mechanisms used by other known ER antagonists. Instead, THC antagonizes ERβ through a novel mechanism we term 'passive antagonism'.
AB - The R,R enantiomer of 5,11-cis-diethyl-5,6,11,12-tetrahydrochrysene-2,8-diol (THC) exerts opposite effects on the transcriptional activity of the two estrogen receptor (ER) subtypes, ERα and ERβ. THC acts as an ERα agonist and as an ERβ antagonist. We have determined the crystal structures of the ERα ligand binding domain (LBD) bound to both THC and a fragment of the transcriptional coactivator GRIP1, and the ERβ LBD bound to THC. THC stabilizes a conformation of the ERα LBD that permits coactivator association and a conformation of the ERβ LBD that prevents coactivator association. A comparison of the two structures, taken together with functional data, reveals that THC does not act on ERβ through the same mechanisms used by other known ER antagonists. Instead, THC antagonizes ERβ through a novel mechanism we term 'passive antagonism'.
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U2 - 10.1038/nsb787
DO - 10.1038/nsb787
M3 - Article
C2 - 11953755
AN - SCOPUS:0036234964
SN - 1072-8368
VL - 9
SP - 359
EP - 364
JO - Nature Structural Biology
JF - Nature Structural Biology
IS - 5
ER -