Abstract
Ligand-dependent activation of transcription by nuclear receptors (NRs) is mediated by interactions with coactivators. Receptor agonists promote coactivator binding, and antagonists block coactivator binding. Here we report the crystal structure of the human estrogen receptor alpha (hER alpha) ligand-binding domain (LBD) bound to both the agonist diethylstilbestrol (DES) and a peptide derived from the NR box II region of the coactivator GRIP1 and the crystal structure of the hER alpha LBD bound to the selective antagonist 4-hydroxytamoxifen (OHT). In the DES-LBD-peptide complex, the peptide binds as a short alpha helix to a hydrophobic groove on the surface of the LBD. In the OHT-LBD complex, helix 12 occludes the coactivator recognition groove by mimicking the interactions of the NR box peptide with the LBD. These structures reveal the two distinct mechanisms by which structural features of OHT promote this "autoinhibitory" helix 12 conformation.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Binding Sites
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Crystallization
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Crystallography, X-Ray
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Diethylstilbestrol / metabolism*
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Diethylstilbestrol / pharmacology
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Estrogen Antagonists / metabolism
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Estrogen Antagonists / pharmacology
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Estrogen Receptor alpha
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Humans
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Mice
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Models, Molecular
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Mutagenesis, Site-Directed
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Nuclear Receptor Coactivator 2
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Peptide Fragments / chemistry
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Peptide Fragments / metabolism
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Protein Binding
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Protein Structure, Secondary
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Receptors, Estrogen / agonists
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Receptors, Estrogen / antagonists & inhibitors
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Receptors, Estrogen / chemistry*
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Receptors, Estrogen / metabolism*
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Structure-Activity Relationship
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Tamoxifen / analogs & derivatives*
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Tamoxifen / metabolism
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Tamoxifen / pharmacology
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Transcription Factors / chemistry
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Transcription Factors / metabolism*
Substances
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Estrogen Antagonists
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Estrogen Receptor alpha
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NCOA2 protein, human
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Ncoa2 protein, mouse
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Nuclear Receptor Coactivator 2
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Peptide Fragments
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Receptors, Estrogen
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Recombinant Fusion Proteins
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Transcription Factors
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Tamoxifen
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afimoxifene
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Diethylstilbestrol