More stable, more estrogenic: the SERM-ERα LBD complex
2011 (English)In: Journal of Biophysical Chemistry, Vol. 2, no 3, 233-243 p.Article in journal (Refereed) Published
Many synthetic selective estrogen receptor mo- dulators (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 in-creased partial agonism of SERMs is associated with increased conformational stability of the SERM-LBD complexes, by investigation of dihy-drobenzoxathiin-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 ex-planation of the counterintuitive results of TAM therapy.
Place, publisher, year, edition, pages
2011. Vol. 2, no 3, 233-243 p.
Breast Cancer; Tamoxifen Resistance; Molecular Dynamics Simulations; Dihydrobenzoxathiin; SERM
IdentifiersURN: urn:nbn:se:kth:diva-78518DOI: 10.4236/jbpc.2011.23029OAI: oai:DiVA.org:kth-78518DiVA: diva2:492578