Characterization of Agonist Binding to His524 in the Estrogen Receptor alpha Ligand Binding Domain
2012 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 116, no 16, 4823-4830 p.Article in journal (Refereed) Published
The bioactivities of the natural steroidal estrogen 17 beta-estradiol (E-2), the synthetic estrogen diethylstilbestrol (DES), and the phytoestrogen genistein (GEN) are intimately associated with their binding to the estrogen receptor alpha ligand binding domain (ER alpha LBD) and accordingly allostery. Molecular modeling techniques have been performed on agonists in complex with the LBD, focusing on the pivotal role of His524 modeled as the epsilon-tautomer and the protonated form (depending on pH). It is found that E-2 binds to the active LBD with the aid of Leu525, showing existing stable patterns of an H-binding network with Glu419 via His524 in all models. The main difference seen in the effect is that the full agonists E-2 and DES have higher binding energies to the protonated His524 than the partial agonists GEN and Way-169916 (W), which is in line with noted experimental transcriptional activities. In conclusion, the study demonstrates that the phytoestrogen GEN interacts differently with the LBD than what E-2 and DES do, which explains the observed signaling differences.
Place, publisher, year, edition, pages
2012. Vol. 116, no 16, 4823-4830 p.
Allostery, Estrogen receptor, Genistein, H-binding, In-line, Ligand binding domain, Molecular modeling techniques, Phytoestrogenes, Protonated, Stable patterns, Steroidal estrogens, Transcriptional activity
IdentifiersURN: urn:nbn:se:kth:diva-95251DOI: 10.1021/jp300895gISI: 000303173800011PubMedID: 22482773ScopusID: 2-s2.0-84860290278OAI: oai:DiVA.org:kth-95251DiVA: diva2:527456
FunderSwedish Research CouncilSwedish e‐Science Research Center
QC 201205212012-05-212012-05-212013-04-08Bibliographically approved