The nature of the ligand-binding pocket of estrogen receptor alpha and beta: The search for subtype-selective ligands and implications for the prediction of estrogenic activity

2003 ◽  
Vol 75 (11-12) ◽  
pp. 2397-2403 ◽  
Author(s):  
J. A. Katzenellenbogen ◽  
R. Muthyala ◽  
B. S. Katzenellenbogen
Keyword(s):  
Estrogen Receptor ◽  
Ligand Binding ◽  
Estrogen Receptor Alpha ◽  
Estrogenic Activity ◽  
Binding Pocket ◽  
Receptor Alpha ◽  
Subtype Selectivity ◽  
Selective Ligands ◽  
Binding Pockets ◽  
Subtype Selective

The ligand-binding pockets of estrogen receptor alpha and beta (ERα and ERβ) appear to have subpockets of different size and flexibility. To find ligands that will discriminate between the two ER subtypes on the basis of affinity or efficacy, we have prepared compounds of varying size, shape and structure. We have evaluated the binding affinity of these compounds and their potency and efficacy as transcriptional activators through ERα and ERβ. In this manner, we have identified a number of ligands that show pronounced ER subtype selectivity. These studies also highlight the eclectic structure–activity relationships of estrogens and the challenges inherent in developing computational methods for the prediction of estrogenic activity.

scholarly journals Molecular Basis for the Subtype Discrimination of the Estrogen Receptor-β-Selective Ligand, Diarylpropionitrile

2003 ◽  
Vol 17 (2) ◽  
pp. 247-258 ◽  
Author(s):  
Jun Sun ◽  
Jerome Baudry ◽  
John A. Katzenellenbogen ◽  
Benita S. Katzenellenbogen
Keyword(s):  
Estrogen Receptor ◽  
Ligand Binding ◽  
Molecular Basis ◽  
Binding Pocket ◽  
Ligand Binding Pocket ◽  
Selective Ligand ◽  
Selective Ligands ◽  
Human Estrogen Receptor ◽  
Subtype Selective ◽  
Selective Character

Abstract Although the two subtypes of the human estrogen receptor (ER), ERα and ERβ, share only 56% amino acid sequence identity in their ligand binding domain (LBD), the residues that surround the ligand are nearly identical; nevertheless, subtype-selective ligands are known. To understand the molecular basis by which diarylpropionitrile (DPN), an ERβ-selective ligand, is able to discriminate between the two ERs, we examined its activity on ER mutants and chimeric constructs generated by DNA shuffling. The N-terminal region of the ERβ LBD (through helix 6) appears to be fully responsible for the ERβ selectivity of DPN. In fact, a single ERα point mutation (L384M) was largely sufficient to switch the DPN response of this ER to that of the ERβ type, but residues in helix 3 are also important in achieving the full ERβ selectivity of DPN. Using molecular modeling, we found an energetically favorable fit for the S-DPN enantiomer in ERβ, in which the proximal phenol mimics the A ring of estradiol, and the nitrile engages in stabilizing interactions with residues in the ligand-binding pocket of ERβ. Our findings highlight that a limited number of critical interactions of DPN with the ERβ ligand-binding pocket underlie its ER subtype-selective character.

Activities of estrogen receptor alpha- and beta-selective ligands at diverse estrogen responsive gene sites mediating transactivation or transrepression

2003 ◽  
Vol 206 (1-2) ◽  
pp. 13-22 ◽  
Author(s):  
William R. Harrington ◽  
Shubin Sheng ◽  
Daniel H. Barnett ◽  
Larry N. Petz ◽  
John A. Katzenellenbogen ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptor Alpha ◽  
Receptor Alpha ◽  
Selective Ligands ◽  
Estrogen Responsive Gene ◽  
Responsive Gene

scholarly journals Estrogenic activity of lignin-derivable alternatives to bisphenol A assessed via molecular docking simulations

RSC Advances ◽  
2021 ◽  
Vol 11 (36) ◽  
pp. 22149-22158
Author(s):  
Alice Amitrano ◽  
Jignesh S. Mahajan ◽  
LaShanda T. J. Korley ◽  
Thomas H. Epps
Keyword(s):  
Estrogen Receptor ◽  
Molecular Docking ◽  
Bisphenol A ◽  
Endocrine Disruptor ◽  
Estrogen Receptor Alpha ◽  
Estrogenic Activity ◽  
Docking Simulations ◽  
Receptor Alpha ◽  
Structure Activity Relationships ◽  
Structure Activity

This article explores lignin-derivable bisphenols as alternatives to bisphenol A – a suspected endocrine disruptor – by investigating their structure-activity relationships with respect to estrogen receptor alpha via molecular docking.

scholarly journals Retrospective Validation of a Structure-Based Virtual Screening Protocol to Identify Ligands for Estrogen Receptor Alpha and Its Application to Identify the Alpha-Mangostin Binding Pose

2014 ◽  
Vol 14 (2) ◽  
pp. 103-108
Author(s):  
Agustina Setiawati ◽  
Florentinus Dika Octa Riswanto ◽  
Sri Hartati Yuliani ◽  
Enade Perdana Istyastono
Keyword(s):  
Estrogen Receptor ◽  
Virtual Screening ◽  
Area Under Curve ◽  
Estrogen Receptor Alpha ◽  
Binding Pocket ◽  
Receiver Operator Characteristic ◽  
Garcinia Mangostana ◽  
Receptor Alpha ◽  
Screening Protocol ◽  
Auc Value

The publicly available enhanced data of ligands and decoys for estrogen receptor alpha (ERα) which were recently published has made the retrospective validation of a structure-based virtual screening (SBVS) protocol to identify ligands for ERα possible. In this article, we present the retrospective validation of an SBVS protocol using PLANTS molecular docking software version 1.2 (PLANTS1.2) as the backbone software. The protocol shows better enrichment factor at 1% false positives (EF1%) value and the Area Under Curve (AUC) value of the Receiver Operator Characteristic (ROC) compared to the original published protocol. Moreover, in all 1000 iterative attempts the protocol could reproduce the co-crystal pose of 4-hydroxitamoxifen in ERα binding pocket. It shows that the protocol is not only able to identify potent ligands for ERα but also able to be employed in examining binding pose of known ligand. Thence, the protocol was successfully employed to examine the binding poses of α-mangostin, an ERα ligand found in the Garcinia mangostana, L. pericarp.

scholarly journals Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Sean W Fanning ◽  
Christopher G Mayne ◽  
Venkatasubramanian Dharmarajan ◽  
Kathryn E Carlson ◽  
Teresa A Martin ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Ligand Binding ◽  
Estrogen Receptor Alpha ◽  
Somatic Mutations ◽  
Conformational Dynamics ◽  
Endocrine Resistance ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Antiestrogen Resistance ◽  
Receptor Alpha

Somatic mutations in the estrogen receptor alpha (ERα) gene (ESR1), especially Y537S and D538G, have been linked to acquired resistance to endocrine therapies. Cell-based studies demonstrated that these mutants confer ERα constitutive activity and antiestrogen resistance and suggest that ligand-binding domain dysfunction leads to endocrine therapy resistance. Here, we integrate biophysical and structural biology data to reveal how these mutations lead to a constitutively active and antiestrogen-resistant ERα. We show that these mutant ERs recruit coactivator in the absence of hormone while their affinities for estrogen agonist (estradiol) and antagonist (4-hydroxytamoxifen) are reduced. Further, they confer antiestrogen resistance by altering the conformational dynamics of the loop connecting Helix 11 and Helix 12 in the ligand-binding domain of ERα, which leads to a stabilized agonist state and an altered antagonist state that resists inhibition.

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