scholarly journals Alternate glucocorticoid receptor ligand binding structures influence outcomes in an in vivo tissue regeneration model

2012 ◽  
Vol 156 (2) ◽  
pp. 121-129 ◽  
Author(s):  
Sumitra Sengupta ◽  
William H. Bisson ◽  
Lijoy K. Mathew ◽  
Siva K. Kolluri ◽  
Robert L. Tanguay
Keyword(s):  
Glucocorticoid Receptor ◽  
Ligand Binding ◽  
Tissue Regeneration ◽  
Receptor Ligand

scholarly journals Doubling the Size of the Glucocorticoid Receptor Ligand Binding Pocket by Deacylcortivazol

2007 ◽  
Vol 28 (6) ◽  
pp. 1915-1923 ◽  
Author(s):  
Kelly Suino-Powell ◽  
Yong Xu ◽  
Chenghai Zhang ◽  
Yong-guang Tao ◽  
W. David Tolbert ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Ligand Binding ◽  
Binding Pocket ◽  
Affinity Binding ◽  
Receptor Ligand ◽  
Ligand Binding Pocket ◽  
Steroid Receptor Coactivator ◽  
High Affinity ◽  
Binding Domains ◽  
Lxxll Motif

ABSTRACT A common feature of nuclear receptor ligand binding domains (LBD) is a helical sandwich fold that nests a ligand binding pocket within the bottom half of the domain. Here we report that the ligand pocket of glucocorticoid receptor (GR) can be continuously extended into the top half of the LBD by binding to deacylcortivazol (DAC), an extremely potent glucocorticoid. It has been puzzling for decades why DAC, which contains a phenylpyrazole replacement at the conserved 3-ketone of steroid hormones that are normally required for activation of their cognate receptors, is a potent GR activator. The crystal structure of the GR LBD bound to DAC and the fourth LXXLL motif of steroid receptor coactivator 1 reveals that the GR ligand binding pocket is expanded to a size of 1,070 Å3, effectively doubling the size of the GR dexamethasone-binding pocket of 540 Å3 and yet leaving the structure of the coactivator binding site intact. DAC occupies only ∼50% of the space of the pocket but makes intricate interactions with the receptor around the phenylpyrazole group that accounts for the high-affinity binding of DAC. The dramatic expansion of the DAC-binding pocket thus highlights the conformational adaptability of GR to ligand binding. The new structure also allows docking of various nonsteroidal ligands that cannot be fitted into the previous structures, thus providing a new rational template for drug discovery of steroidal and nonsteroidal glucocorticoids that can be specifically designed to reach the unoccupied space of the expanded pocket.

Enhancing the Stability and Solubility of the Glucocorticoid Receptor Ligand-Binding Domain by High-Throughput Library Screening

2010 ◽  
Vol 403 (4) ◽  
pp. 562-577 ◽  
Author(s):  
Tobias Seitz ◽  
Ralf Thoma ◽  
Guillaume A. Schoch ◽  
Martine Stihle ◽  
Jörg Benz ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Ligand Binding ◽  
High Throughput ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Library Screening ◽  
Receptor Ligand ◽  
The Stability

scholarly journals Quantitative Imaging of Receptor-Ligand Engagement in Intact Live Animals

2017 ◽  
Author(s):  
Alena Rudkouskaya ◽  
Nattawut Sinsuebphon ◽  
Jamie Ward ◽  
Kate Tubbesing ◽  
Xavier Intes ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Ex Vivo ◽  
Resonance Energy ◽  
Receptor Expression ◽  
Whole Body ◽  
Systemic Delivery ◽  
Receptor Ligand ◽  
Intracellular Drug Delivery ◽  
Targeted Drug

Maintaining an intact tumor environment is critical for quantitation of receptor-ligand engagement in a targeted drug development pipeline. However, measuring receptor-ligand engagement in vivo and non-invasively in preclinical settings is extremely challenging. We found that quantitation of intracellular receptor-ligand binding can be achieved using whole-body macroscopic lifetime-based Förster Resonance Energy Transfer (FRET) imaging in intact, live animals bearing tumor xenografts. We determined that FRET levels report on ligand binding to transferrin receptors conversely to raw fluorescence intensity. We then established that FRET levels in heterogeneous tumors correlate with intracellular ligand binding but strikingly, not with ubiquitously used ex vivo receptor expression assessment. Hence, MFLI-FRET provides a direct measurement of systemic delivery, target availability and intracellular drug delivery in intact animals. Here, we have used MFLI to measure FRET longitudinally in intact animals for the first time. MFLI-FRET is well–suited for guiding the development of targeted drug therapy in heterogeneous intact, live small animals.

scholarly journals Ligand-receptor binding kinetics in drug design

2020 ◽  
Vol 66 (1) ◽  
pp. 42-53
Author(s):  
D.V. Borisov ◽  
A.V. Veselovsky
Keyword(s):  
Ligand Binding ◽  
Receptor Binding ◽  
Rational Design ◽  
Drug Binding ◽  
New Drugs ◽  
Receptor Ligand ◽  
Molecular Features ◽  
Kinetics Of

Traditionally, the thermodynamic values of affinity are considered as the main criterion for the development of new drugs. Usually, these values for drugs are measured in vitro at steady concentrations of the receptor and ligand, which are differed from in vivo environment. Recent studies have shown that the kinetics of the process of drug binding to its receptor make significant contribution in the drug effectiveness. This has increased attention in characterizing and predicting the rate constants of association and dissociation of the receptor ligand at the stage of preclinical studies of drug candidates. A drug with a long residence time can determine ligand-receptor selectivity (kinetic selectivity), maintain pharmacological activity of the drug at its low concentration in vivo. The paper discusses the theoretical basis of protein-ligand binding, molecular determinants that control the kinetics of the drug-receptor binding. Understanding the molecular features underlying the kinetics of receptor-ligand binding will contribute to the rational design of drugs with desired properties.

scholarly journals Crystal Structure of the Glucocorticoid Receptor Ligand Binding Domain Reveals a Novel Mode of Receptor Dimerization and Coactivator Recognition

Cell ◽  
2002 ◽  
Vol 110 (1) ◽  
pp. 93-105 ◽  
Author(s):  
Randy K. Bledsoe ◽  
Valerie G. Montana ◽  
Thomas B. Stanley ◽  
Chris J. Delves ◽  
Christopher J. Apolito ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Glucocorticoid Receptor ◽  
Ligand Binding ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Receptor Ligand ◽  
Receptor Dimerization

scholarly journals LGD-5552, an Antiinflammatory Glucocorticoid Receptor Ligand with Reduced Side Effects, in Vivo

Endocrinology ◽  
2008 ◽  
Vol 149 (5) ◽  
pp. 2080-2089 ◽  
Author(s):  
Francisco J. López ◽  
Robert J. Ardecky ◽  
Bruce Bebo ◽  
Khalid Benbatoul ◽  
Louise De Grandpre ◽  
...  
Keyword(s):  
Side Effects ◽  
Glucocorticoid Receptor ◽  
Therapeutic Window ◽  
Glucocorticoid Treatment ◽  
Receptor Ligand ◽  
Monocyte Chemoattractant Protein 1 ◽  
Inflammatory Conditions ◽  
Differential Gene Regulation ◽  
Antiinflammatory Effects

Treatment of inflammation is often accomplished through the use of glucocorticoids. However, their use is limited by side effects. We have examined the activity of a novel glucocorticoid receptor ligand that binds the receptor efficiently and strongly represses inflammatory gene expression. This compound has potent antiinflammatory activity in vivo and represses the transcription of the inflammatory cytokine monocyte chemoattractant protein-1 and induces the antiinflammatory cytokine IL-10. The compound demonstrates differential gene regulation, compared with commonly prescribed glucocorticoids, effectively inducing some genes and repressing others in a manner different from the glucocorticoid prednisolone. The separation between the antiinflammatory effects of LGD-5552 and the side effects commonly associated with glucocorticoid treatment suggest that this molecule differs significantly from prednisolone and other steroids and may provide a safer therapeutic window for inflammatory conditions now commonly treated with steroidal glucocorticoids.

scholarly journals A Natural Mutation in Helix 5 of the Ligand Binding Domain of Glucocorticoid Receptor Enhances Receptor-Ligand Interaction

PLoS ONE ◽  
2016 ◽  
Vol 11 (10) ◽  
pp. e0164628 ◽  
Author(s):  
Henry Reyer ◽  
Siriluck Ponsuksili ◽  
Ellen Kanitz ◽  
Ralf Pöhland ◽  
Klaus Wimmers ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Ligand Binding ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Ligand Interaction ◽  
Receptor Ligand ◽  
Natural Mutation
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