Structural Analysis on the Pathologic Mutant Glucocorticoid Receptor Ligand-Binding Domains
Glucocorticoid receptor (GR) gene mutations may cause familial or sporadic generalized glucocorticoid resistance syndrome. Most of the missense forms distribute in the ligand-binding domain and impair its ligand-binding activity and formation of the activation function (AF)-2 that binds LXXLL motif-containing coactivators. We performed molecular dynamics simulations to ligand-binding domain of pathologic GR mutants to reveal their structural defects. Several calculated parameters including interaction energy for dexamethasone or the LXXLL peptide indicate that destruction of ligand-binding pocket (LBP) is a primary character. Their LBP defects are driven primarily by loss/reduction of the electrostatic interaction formed by R611 and T739 of the receptor to dexamethasone and a subsequent conformational mismatch, which deacylcortivazol resolves with its large phenylpyrazole moiety and efficiently stimulates transcriptional activity of the mutant receptors with LBP defect. Reduced affinity of the LXXLL peptide to AF-2 is caused mainly by disruption of the electrostatic bonds to the noncore leucine residues of this peptide that determine the peptide's specificity to GR, as well as by reduced noncovalent interaction against core leucines and subsequent exposure of the AF-2 surface to solvent. The results reveal molecular defects of pathologic mutant receptors and provide important insights to the actions of wild-type GR.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2016 |
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| Erschienen: |
2016 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:30 |
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| Enthalten in: |
Molecular endocrinology (Baltimore, Md.) - 30(2016), 2 vom: 15. Feb., Seite 173-88 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Hurt, Darrell E [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 31.10.2016 Date Revised 20.12.2019 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1210/me.2015-1177 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM256270848 |
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| 100 | 1 | |a Hurt, Darrell E |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Structural Analysis on the Pathologic Mutant Glucocorticoid Receptor Ligand-Binding Domains |
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| 500 | |a Date Completed 31.10.2016 | ||
| 500 | |a Date Revised 20.12.2019 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Glucocorticoid receptor (GR) gene mutations may cause familial or sporadic generalized glucocorticoid resistance syndrome. Most of the missense forms distribute in the ligand-binding domain and impair its ligand-binding activity and formation of the activation function (AF)-2 that binds LXXLL motif-containing coactivators. We performed molecular dynamics simulations to ligand-binding domain of pathologic GR mutants to reveal their structural defects. Several calculated parameters including interaction energy for dexamethasone or the LXXLL peptide indicate that destruction of ligand-binding pocket (LBP) is a primary character. Their LBP defects are driven primarily by loss/reduction of the electrostatic interaction formed by R611 and T739 of the receptor to dexamethasone and a subsequent conformational mismatch, which deacylcortivazol resolves with its large phenylpyrazole moiety and efficiently stimulates transcriptional activity of the mutant receptors with LBP defect. Reduced affinity of the LXXLL peptide to AF-2 is caused mainly by disruption of the electrostatic bonds to the noncore leucine residues of this peptide that determine the peptide's specificity to GR, as well as by reduced noncovalent interaction against core leucines and subsequent exposure of the AF-2 surface to solvent. The results reveal molecular defects of pathologic mutant receptors and provide important insights to the actions of wild-type GR | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Carrier Proteins |2 NLM | |
| 650 | 7 | |a GRIP1 protein, human |2 NLM | |
| 650 | 7 | |a Ligands |2 NLM | |
| 650 | 7 | |a Mutant Proteins |2 NLM | |
| 650 | 7 | |a Nerve Tissue Proteins |2 NLM | |
| 650 | 7 | |a Peptides |2 NLM | |
| 650 | 7 | |a Pregnatrienes |2 NLM | |
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| 700 | 1 | |a Suzuki, Shigeru |e verfasserin |4 aut | |
| 700 | 1 | |a Mayama, Takafumi |e verfasserin |4 aut | |
| 700 | 1 | |a Charmandari, Evangelia |e verfasserin |4 aut | |
| 700 | 1 | |a Kino, Tomoshige |e verfasserin |4 aut | |
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