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Characterization of Agonist Binding to His524 in the Estrogen Receptor alpha Ligand Binding Domain
KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.ORCID iD: 0000-0001-8198-9284
KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.ORCID iD: 0000-0002-1763-9383
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
Abstract [en]

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.
Keyword [en]
Allostery, Estrogen receptor, Genistein, H-binding, In-line, Ligand binding domain, Molecular modeling techniques, Phytoestrogenes, Protonated, Stable patterns, Steroidal estrogens, Transcriptional activity
National Category
Physical Chemistry
URN: urn:nbn:se:kth:diva-95251DOI: 10.1021/jp300895gISI: 000303173800011PubMedID: 22482773ScopusID: 2-s2.0-84860290278OAI: diva2:527456
Swedish Research CouncilSwedish e‐Science Research Center

QC 20120521

Available from: 2012-05-21 Created: 2012-05-21 Last updated: 2013-04-08Bibliographically approved
In thesis
1. Theoretical Studies of Anti-cancer Drug Tamoxifen and Estrogen Receptor Alpha
Open this publication in new window or tab >>Theoretical Studies of Anti-cancer Drug Tamoxifen and Estrogen Receptor Alpha
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

For decades tamoxifen (TAM) has been widely used for treatment of breast cancer by mediating mainly the estrogen receptor α (ERα) signaling pathways, whereby it suppresses estrogen stimulated cancer cell growth. The clinical response of TAM has been linked to cytochrome P450 2D6 (CYP2D6), which is the main isoform responsible for the conversion of TAM to the active metabolites 4-hydroxyTAM (OHT) and endoxifen. Numerous clinical studies have thus attempted to assess the effects of CYP2D6 genetic variants on patients treated by TAM. However, the studies have resulted in contradictive conclusions. This thesis focuses on computational investigations of TAM and its main target ERα. The results obtained describe how the ligands contact with the ERα ligand binding domain (LBD), and provide possible mechanisms responsible for the CYP2D6 activating in TAM treatment. In addition, the CYP-mediated biotransformation of TAM-like compounds is investigated. All studies in this thesis aim to a step towards developing improved therapeutic agents for breast cancer treatment. In paper I, molecular dynamics simulations of ligand-LBD complexes have been performed. The results indicate that although OHT is a high affinity metabolite, it may have more undesired estrogen-like properties than the parent drug TAM, as a consequence of the additional 4-hydroxy group. In papers II and V, quantum mechanics calculations have been performed to study how the ligands are bound to ERα LBD. It is found that different conformational isomers of TAM-like ligands are discriminated by the LBD. The interactions between ligands and His524-Leu525 in the LBD are correlated with the transcriptional activity of estrogen agonist compounds. In papers III and IV, different CYP-mediated biotransformations of TAM and derivatives are studied. Based on the results from the computations, we suggest two modified compounds which are highly possible to be activated by other CYP isoforms besides CYP2D6, thereby avoiding CYP2D6 genetic polymorphism. Overall, the results generally agree with the hitherto available experimental results. Further experimental studies are needed to verify the proposed principles of ligands signaling through ERα, and to test the suggested CYP-mediated reactions and the bioactivity of the modified compounds.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2012. vi, 58 p.
Trita-BIO-Report, ISSN 1654-2312 ; 2012:23
National Category
Theoretical Chemistry
urn:nbn:se:kth:diva-105721 (URN)978-91-7501-586-6 (ISBN)
Public defence
2012-12-18, FB53, Albanova Universitetscentrum, Stockholm, 14:00 (English)

QC 20121126

Available from: 2012-11-26 Created: 2012-11-23 Last updated: 2012-11-26Bibliographically approved

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