The Structural Basis of Estrogen Receptor/Coactivator Recognition and the Antagonism of This Interaction by Tamoxifen

@article{Shiau1998TheSB,
  title={The Structural Basis of Estrogen Receptor/Coactivator Recognition and the Antagonism of This Interaction by Tamoxifen},
  author={Andrew K. Shiau and Danielle Barstad and Paula M. Loria and Lin Cheng and Peter J. Kushner and David A. Agard and Geoffrey L. Greene},
  journal={Cell},
  year={1998},
  volume={95},
  pages={927-937}
}
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… Expand
A second binding site for hydroxytamoxifen within the coactivator-binding groove of estrogen receptor beta.
TLDR
The results provide a direct demonstration of two binding sites for HT in ERbeta, as has been previously suggested for ERalpha by using biochemical methods, and represent a crystal structure of a small nonpeptide molecule occupying the coactivator recognition site. Expand
Molecular Determinants of the Estrogen Receptor-Coactivator Interface
TLDR
The recruitment of p160 coactivators to the estrogen receptor is likely to depend not only on the LXXLL motif making hydrophobic interactions with the docking surface on the receptors, but also on adjacent basic residues, which may be involved in the recognition of charged residues on the receptor to allow the initial docking of the motif. Expand
Interaction of Transcriptional Intermediary Factor 2 Nuclear Receptor Box Peptides with the Coactivator Binding Site of Estrogen Receptor α*
TLDR
Analysis of the binding properties of wild type NR box peptides, as well as mutant peptides designed to probe the Box B3 orientation, suggests that the box B3 peptide primarily adopts the “classical” LXXLL orientation in solution. Expand
Full-length estrogen receptor α and its ligand-binding domain adopt different conformations upon binding ligand
  • A. Bapat, D. Frail
  • Chemistry, Medicine
  • The Journal of Steroid Biochemistry and Molecular Biology
  • 2003
TLDR
The ability of a ligand to induce a strong interaction of pepalphaII with the estrogen receptor alpha ligand-binding domain predicts that the ligand will have greater antagonist activity on the full-length receptor. Expand
Implications of the binding of tamoxifen to the coactivator recognition site of the estrogen receptor.
TLDR
The biological reports leading up to the structural conformation of a second ER ligand-binding site are summarized, the ERbeta LBD structure bound with two HT molecules to other ER structures are compared, and the potential for small molecular inhibitors designed to directly inhibit ER- coactivator and nuclear receptor (NR)-coactivator interactions are discussed. Expand
Chapter 244 – Nuclear Receptor Coactivators
Publisher Summary This chapter highlights the general mechanisms for coactivator complexes that enhance nuclear receptor (NR) gene activation and explains the ligand-dependent interaction betweenExpand
Structural insights into the mode of action of a pure antiestrogen.
TLDR
The novel observation that binding of ICI results in the complete destabilization of H12 provides some indications as to a possible mechanism for pure receptor antagonism. Expand
Structural Basis for Ligand Activity in VDR
Publisher Summary The ligand-binding domain (LBD) of nuclear receptors harbors a highly structured ligand-dependent activation function or AF-2, a major interface for dimerization with RXR and anExpand
Structural and functional evidence for ligand-independent transcriptional activation by the estrogen-related receptor 3.
The crystal structure of the ligand binding domain (LBD) of the estrogen-related receptor 3 (ERR3) complexed with a steroid receptor coactivator-1 (SRC-1) peptide reveals a transcriptionally activeExpand
Structural and biochemical mechanisms for the specificity of hormone binding and coactivator assembly by mineralocorticoid receptor.
TLDR
This work reports a crystal structure of the MR ligand binding domain containing a single C808S mutation bound to corticosterone and the fourth LXXLL motif of steroid receptor coactivator-1 (SRC1-4) and reveals a compact steroid binding pocket with a unique topology that is primarily defined by key residues of helices 6 and 7. Expand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 96 REFERENCES
A canonical structure for the ligand-binding domain of nuclear receptors
TLDR
Mutant studies support a general mechanism for ligand-induced activation deduced from the comparison of the transcriptionally active RARγ holo- and inactive RXRα apo-LBD structures. Expand
AF-2 activity and recruitment of steroid receptor coactivator 1 to the estrogen receptor depend on a lysine residue conserved in nuclear receptors
TLDR
It is shown that a lysine residue, which is conserved in most nuclear receptors in the predicted helix 3, is also required for estrogen-dependent transactivation, and proposed that it is required, together with residues in helix 12, to form the surface by which members of the nuclear receptor family interact with coactivators. Expand
Crystallographic comparison of the estrogen and progesterone receptor's ligand binding domains.
TLDR
A peculiar crystal packing event displaces helix 12 in the hERalphaLBD reported here, suggesting a higher degree of dynamic variability than expected for this critical substructure. Expand
Enhancement of Estrogen Receptor Transcriptional Activity by the Coactivator GRIP-1 Highlights the Role of Activation Function 2 in Determining Estrogen Receptor Pharmacology*
TLDR
It is likely, therefore, that the C-terminal AF-2 domain may function as a molecular switch allowing the wild-type receptor to discriminate between agonists and antagonists as well as providing a surface with which associated proteins can interact. Expand
Molecular basis of agonism and antagonism in the oestrogen receptor
TLDR
The crystal structures of the LBD of ER in complex with the endogenous oestrogen, 17β-oestradiol, and the selective antagonist raloxifene provide a molecular basis for the distinctive pharmacophore of the ER and its catholic binding properties. Expand
Structure and specificity of nuclear receptor-coactivator interactions.
TLDR
Biochemical and crystallographic analyses revealed that hormone binding leads to the formation of a hydrophobic groove within the ligand binding domain of the thyroid hormone receptor that interacts with an LxxLL motif-containing alpha-helix from GRIP1, a coactivator, suggesting that these common structural elements impart flexibility to combinatorial regulation, whereas side chains at the interface impart specificity. Expand
Hormone-dependent coactivator binding to a hydrophobic cleft on nuclear receptors.
TLDR
Scanning surface mutagenesis on the human thyroid hormone receptor was performed to define the site that binds the coactivators, glucocorticoid receptor-interacting protein 1 (GRIP1) and steroid receptor coactivator 1 (SRC-1). Expand
Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-γ
TLDR
A general mechanism for the assembly of nuclear receptors with co-activators is suggested, based on the observation that two consecutive LXXLL motifs of SRC-1 make identical contacts with both subunits of a PPAR-γ homodimer. Expand
The nuclear receptor ligand-binding domain: structure and function.
TLDR
The concomitant identification and functional analysis of co-regulators (transcriptional intermediary factors [TIFs], comprising co-activators and co-repressors) previously predicted from squelching studies have deepened this understanding. Expand
Crystal structure of the RAR-γ ligand-binding domain bound to all-trans retinoic acid
The 2.0-Å crystal structure of the ligand-binding domain (LBD) of the human retinoic acid receptor (RAR)-γ bound to all-trans retinoic acid reveals the ligand-binding interactions and suggests anExpand
...
1
2
3
4
5
...