Structural characterization of a subtype-selective ligand reveals a novel mode of estrogen receptor antagonism.
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, ER alpha and ER beta. THC acts as an ER alpha agonist and as an ER beta antagonist. We have determined the crystal structures of the ER alpha ligand binding domain (LBD) bound to both THC and a fragment of the transcriptional coactivator GRIP1, and the ER beta LBD bound to THC. THC stabilizes a conformation of the ER alpha LBD that permits coactivator association and a conformation of the ER beta LBD that prevents coactivator association. A comparison of the two structures, taken together with functional data, reveals that THC does not act on ER beta through the same mechanisms used by other known ER antagonists. Instead, THC antagonizes ER beta through a novel mechanism we term 'passive antagonism'.
Shiau
Andrew K
AK
The Howard Hughes Medical Institute and Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143, USA.
Barstad
Danielle
D
Radek
James T
JT
Meyers
Marvin J
MJ
Nettles
Kendall W
KW
Katzenellenbogen
Benita S
BS
Katzenellenbogen
John A
JA
Agard
David A
DA
Greene
Geoffrey L
GL
D001665:Binding Sites; D002911:Chrysenes / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D051958:Nuclear Receptor Coactivator 2; D010446:Peptide Fragments / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011960:Receptors, Estrogen / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism
C120076:5,11-diethyl-5,6,11,12-tetrahydrochrysene-2,8-diol; D002911:Chrysenes; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008024:Ligands; C498001:NCOA2 protein, human; D051958:Nuclear Receptor Coactivator 2; D010446:Peptide Fragments; D011960:Receptors, Estrogen; D014157:Transcription Factors