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Brzozowski, A.M., Pike, A.C., Dauter, Z., Hubbard, R.E., Bonn, T., Engstrom, O., Ohman, L., Greene, G.L., Gustafsson, J.A. and Carlquist, M. (1997) Molecular basis of agonism and antagonism in the oestrogen receptor. Nature, 389, 753-758. doi:10.1038/39645

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• TITLE: More Stable, More Estrogenic: The SERM-ERα LBD Complex

  AUTHORS: Li Gao, Yaoquan Tu, Leif A. Eriksson

  KEYWORDS: Breast Cancer; Tamoxifen Resistance; Molecular Dynamics Simulations; Dihydrobenzoxathiin; SERM

  JOURNAL NAME: Journal of Biophysical Chemistry, Vol.2 No.3, August 9, 2011

  ABSTRACT: Many synthetic selective estrogen receptor modulators (SERMs) have been cocrystallized with the human estrogen receptor α ligand binding domain (ERα LBD). Despite stabilizing the same canonical inactive conformation of the LBD, most SERMs display different ligand-dependent pharmacological profiles. We show here that increased partial agonism of SERMs is associated with increased conformational stability of the SERM-LBD complexes, by investigation of dihydrobenzoxathiin-based SERMs using molecular modelling techniques. Analyses of tamoxifen (TAM) and 4-hydroxytamoxifen (OHT) in complex with the LBD furthermore indicates that the conversion of TAM to OHT increases both the affinity to ERα and the partial agonism of the anti-cancer drug, which provides a plausible explanation of the counterintuitive results of TAM therapy.