Estrogen Receptor Microarrays:  Subtype-Selective Ligand Binding

2004 ◽  
Vol 126 (15) ◽  
pp. 4754-4755 ◽  
Author(s):  
Sung Hoon Kim ◽  
Anobel Tamrazi ◽  
Kathryn E. Carlson ◽  
Jonathan R. Daniels ◽  
In Young Lee ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Ligand Binding ◽  
Selective Ligand ◽  
Subtype Selective

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.

Structural characterization of a subtype-selective ligand reveals a novel mode of estrogen receptor antagonism

2002 ◽  
Author(s):  
Andrew K. Shiau ◽  
Danielle Barstad ◽  
James T. Radek ◽  
Marvin J. Meyers ◽  
Kendall W. Nettles ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Structural Characterization ◽  
Receptor Antagonism ◽  
Selective Ligand ◽  
Subtype Selective

scholarly journals Aspartate mutation distinguishes ETA but not ETB receptor subtype-selective ligand binding while abolishing phospholipase C activation in both receptors

FEBS Letters ◽  
1995 ◽  
Vol 361 (2-3) ◽  
pp. 243-249 ◽  
Author(s):  
Patricia M. Rose ◽  
Stanley R. Krystek ◽  
Pramathesh S. Patel ◽  
Eddie C.K. Liu ◽  
Jean S. Lynch ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Phospholipase C ◽  
Receptor Subtype ◽  
Selective Ligand ◽  
Etb Receptor ◽  
Subtype Selective

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 The effect of protein mutations on drug binding suggests ensuing personalised drug selection

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shunzhou Wan ◽  
Deepak Kumar ◽  
Valentin Ilyin ◽  
Ussama Al Homsi ◽  
Gulab Sher ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Ligand Binding ◽  
Binding Free Energy ◽  
Personalised Medicine ◽  
Clinical Decision ◽  
Drug Binding ◽  
Dynamics Simulation ◽  
Breast Cancer Patients ◽  
Natural Ligand ◽  
Affinity Interaction

AbstractThe advent of personalised medicine promises a deeper understanding of mechanisms and therefore therapies. However, the connection between genomic sequences and clinical treatments is often unclear. We studied 50 breast cancer patients belonging to a population-cohort in the state of Qatar. From Sanger sequencing, we identified several new deleterious mutations in the estrogen receptor 1 gene (ESR1). The effect of these mutations on drug treatment in the protein target encoded by ESR1, namely the estrogen receptor, was achieved via rapid and accurate protein–ligand binding affinity interaction studies which were performed for the selected drugs and the natural ligand estrogen. Four nonsynonymous mutations in the ligand-binding domain were subjected to molecular dynamics simulation using absolute and relative binding free energy methods, leading to the ranking of the efficacy of six selected drugs for patients with the mutations. Our study shows that a personalised clinical decision system can be created by integrating an individual patient’s genomic data at the molecular level within a computational pipeline which ranks the efficacy of binding of particular drugs to variant proteins.

Simulations of the Estrogen Receptor Ligand-Binding Domain:  Affinity of Natural Ligands and Xenoestrogens

2000 ◽  
Vol 43 (24) ◽  
pp. 4594-4605 ◽  
Author(s):  
B. Chris Oostenbrink ◽  
Jed W. Pitera ◽  
Marola M. H. van Lipzig ◽  
John H. N. Meerman ◽  
Wilfred F. van Gunsteren
Keyword(s):  
Estrogen Receptor ◽  
Ligand Binding ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Receptor Ligand ◽  
Natural Ligands ◽  
Estrogen Receptor Ligand
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