An in silico study to search for human estrogen receptor-alpha dimerization motif(s)
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The human estrogen receptor (ER) is a ligand-based gene transcription factor. Upon binding with an estrogenic (agonist) ligand, ER undergoes conformational changes which promote binding of co-activator proteins, an essential condition for gene transcription. Signal transmitting co-activator proteins bound to the ER dimer initiate the transcription of target genes. In the presence of an antagonist, induced conformational changes on the ER prevent co-activator binding and block the signaling cascade of hormone-dependent ER transactivation. However, it was observed that breast cancers that initially respond well to antagonist by growth cessation or regression eventually resume growth despite the continued presence of the antagonist and most antagonist-resistant tumors continue to express ER. Thus, a hormone independent activation pathway might be responsible for antagonist resistance. This situation prompts us to look for and design new therapeutic strategies. Targeting the ERa dimerization interface, we have identified three sequences where sequence I of monomer A binds with sequence-II of monomer Band vice-versa; sequence-III of monomer A binds with sequence-III of monomer-B. We also observed that upon activation with an estrogenic ligand, ER monomers interact more strongly with each other. Finally, to find a peptide-based inhibitor of ERa, we chose sequence-II which is hydrophilic in nature and more stable than sequence-I which is hydrophobic in nature. Using sequence-II as a template, we further designed a variant of that peptide by modulating the electrostatic potential by in silico mutation. Molecular dynamics reveal that the designed peptide binds in the groove formed by HELIX 10 and HELIX 11 in the ligand binding domain (LBD) ofERa, mimicking ER dimerization. Our study reveals that sequence-II can be treated as a template where further structure based design can be performed to obtain a suitable inhibitor for ERa dimerization required for gene transcription.
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