title: Simulations reveal increased fluctuations in estrogen receptor-alpha conformation upon antagonist binding.
abstract: Molecular dynamics (MD) simulations have been used to model dynamic fluctuations in the structure of estrogen receptor-alpha (ER-α) upon binding to the natural agonist 17β-estradiol (E2) and to the active metabolite of the breast cancer drug and antagonist, 4-hydroxytamoxifen (OHT). We present the most extensive MD simulations to date of ER-α, with over 1μs of combined simulations for the monomer and dimer forms. Simulations reveal that the antagonist-bound complex includes significant fluctuations while the agonist-bound complex is tightly restrained. OHT increases dynamic disorder in the loops located to either side of the tail H12 helix; H12 has been associated with the activation status of ER-α. We also report that fluctuations near H12 lead to greater conformational variation in the binding mode of the ethylamine tail of OHT. Both the agonist and antagonist conformations are stable throughout the 240ns simulations, supporting the hypothesis that there are no transitions between these two states or into intermediate states. The stable position of H12 in the OHT-bound conformation suggests that OHT stabilizes a well-defined antagonist conformational ensemble rather than merely blocking the agonist-driven activation of ER-α. Simultaneously, the increased dynamic properties of the OHT-bound complex is a potential source of binding entropy.
authors: University of Hawaii at Manoa, Department of Chemistry, University of Hawaii Cancer Center, United States. Electronic address: hng@hawaii.edu.
authors: Ho Leung
authors: HL
authors: Ng
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D004958:Estradiol / Q000737:chemistry / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D017433:Protein Structure, Secondary; D013629:Tamoxifen / Q000737:chemistry / Q000378:metabolism
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D008024:Ligands; D013629:Tamoxifen; D004958:Estradiol
keywords: Drug binding; Estrogen receptor; Hormone receptor; Molecular dynamics