Molecular Basis of the Interaction Specificity between the Human Glucocorticoid Receptor and Its Endogenous Steroid Ligand Cortisol
Identifieur interne : 000A14 ( Main/Curation ); précédent : 000A13; suivant : 000A15Molecular Basis of the Interaction Specificity between the Human Glucocorticoid Receptor and Its Endogenous Steroid Ligand Cortisol
Auteurs : Johannes Von Langen [Allemagne] ; Karl Einrich Fritzemeier [Allemagne] ; Stephan Diekmann [Allemagne] ; Alexander Hillisch [Allemagne]Source :
- ChemBioChem [ 1439-4227 ] ; 2005-06-06.
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Abstract
We analyzed the binding of five steroids to the human glucocorticoid receptor (hGR) experimentally as well as theoretically. In vitro, we measured the binding affinity of aldosterone, cortisol, estradiol, progesterone, and testosterone to hGR in competition with the ligand dexamethasone. The binding affinity relative to the endogenous ligand cortisol (100 %) is reduced for progesterone (22 %) and aldosterone (20 %) and is very weak for testosterone (1.5 %) and estradiol (0.2 %). In parallel, we constructed a homology model of the hGR ligand‐binding domain (LBD) based on the crystal structure of the human progesterone receptor (hPR). After docking the five steroids into the hGR model ligand‐binding pocket, we performed five separate 4‐ns molecular dynamics (MD) simulations with these complexes in order to study the complex structures. We calculated the binding affinities with two different approaches (MM/PBSA, FlexX) and compared them with the values of the experimentally determined relative binding affinities. Both theoretical methods allowed discrimination between strongly and weakly binding ligands and recognition of cortisol as the endogenous ligand of the hGR in silico. Cortisol binds most strongly due to a nearly perfect steric and electrostatic complementarity with the hGR binding pocket. Chemically similar ligands such as estradiol, testosterone, and progesterone also fit into the hGR binding pocket, but they are unable to form all those contacts with the amino acids of the protein that are necessary to yield a stable, transcriptionally active receptor conformation. Our analysis thus explains the selectivity of the human glucocorticoid receptor for its endogenous ligand cortisol at a molecular level.
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DOI: 10.1002/cbic.200400361
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<front><div type="abstract" xml:lang="en">We analyzed the binding of five steroids to the human glucocorticoid receptor (hGR) experimentally as well as theoretically. In vitro, we measured the binding affinity of aldosterone, cortisol, estradiol, progesterone, and testosterone to hGR in competition with the ligand dexamethasone. The binding affinity relative to the endogenous ligand cortisol (100 %) is reduced for progesterone (22 %) and aldosterone (20 %) and is very weak for testosterone (1.5 %) and estradiol (0.2 %). In parallel, we constructed a homology model of the hGR ligand‐binding domain (LBD) based on the crystal structure of the human progesterone receptor (hPR). After docking the five steroids into the hGR model ligand‐binding pocket, we performed five separate 4‐ns molecular dynamics (MD) simulations with these complexes in order to study the complex structures. We calculated the binding affinities with two different approaches (MM/PBSA, FlexX) and compared them with the values of the experimentally determined relative binding affinities. Both theoretical methods allowed discrimination between strongly and weakly binding ligands and recognition of cortisol as the endogenous ligand of the hGR in silico. Cortisol binds most strongly due to a nearly perfect steric and electrostatic complementarity with the hGR binding pocket. Chemically similar ligands such as estradiol, testosterone, and progesterone also fit into the hGR binding pocket, but they are unable to form all those contacts with the amino acids of the protein that are necessary to yield a stable, transcriptionally active receptor conformation. Our analysis thus explains the selectivity of the human glucocorticoid receptor for its endogenous ligand cortisol at a molecular level.</div>
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