共查询到20条相似文献,搜索用时 31 毫秒
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Christian Köhler Göran Carlström Stefan Tångefjord Tineke Papavoine Matti Lepistö Karl Edman Mikael Akke 《Biomolecular NMR assignments》2018,12(2):263-268
The glucocorticoid receptor (GR) is a nuclear hormone receptor that regulates key genes controlling development, metabolism, and the immune response. GR agonists are efficacious for treatment of inflammatory, allergic, and immunological disorders. Steroid hormone binding to the ligand-binding domain (LBD) of GR is known to change the structural and dynamical properties of the receptor, which in turn control its interactions with DNA and various co-regulators and drive the pharmacological response. Previous biophysical studies of the GR LBD have required the use of mutant forms to overcome issues with limited protein stability and high aggregation propensity. However, these mutant variants are known to also influence the functional response of the receptor. Here we report a successful protocol for protein expression, purification, and NMR characterization of the wildtype human GR LBD. We achieved chemical shift assignments for 90% of the LBD backbone resonances, with 216 out of 240 non-proline residues assigned in the 1H–15N TROSY spectrum. These advancements form the basis for future investigations of allosteric effects in GR signaling. 相似文献
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Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition 总被引:29,自引:0,他引:29
Bledsoe RK Montana VG Stanley TB Delves CJ Apolito CJ McKee DD Consler TG Parks DJ Stewart EL Willson TM Lambert MH Moore JT Pearce KH Xu HE 《Cell》2002,110(1):93-105
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Her S Patel PD Schatzberg AF Lyons DM 《The Journal of steroid biochemistry and molecular biology》2005,94(4):319-326
To identify the determinants of impaired glucocorticoid receptor (GR) signaling in a model of glucocorticoid resistance, cloned GR from Guyanese squirrel monkeys (gsmGR) was tagged with enhanced green fluorescent protein, and nuclear translocation was examined in transfected COS1 cells. In keeping with evidence that gsmGR transactivational competence is impaired, we found that nuclear translocation is likewise diminished in gsmGR relative to human GR (hGR). Experiments with GR chimeras revealed that replacement of the gsmGR ligand binding domain (LBD) with that from hGR increased translocation. Truncated gsmGR constructs lacking the LDB after amino acid 552 also showed increased translocation even in the absence of cortisol. Three back-mutations of gsmGR to hGR (Thr551Ser, Ala616Ser, and Ser618Ala) in the LBD confirmed that these amino acids play a role in diminished translocation. 相似文献
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Zhuang Jin Hua Lin Sathish Srinivasan Jerome C. Nwachukwu Nelson Bruno Patrick R. Griffin Kendall W. Nettles Theodore M. Kamenecka 《Bioorganic & medicinal chemistry letters》2017,27(2):347-353
Adverse effects of glucocorticoids could be limited by developing new compounds that selectively modulate anti-inflammatory activity of the glucocorticoid receptor (GR). We have synthesized a novel series of steroidal GR ligands, including potent agonists, partial agonists and antagonists with a wide range of effects on inhibiting secretion of interleukin-6. Some of these new ligands were designed to directly impact conformational stability of helix-12, in the GR ligand-binding domain (LBD). These compounds modulated GR activity and glucocorticoid-induced gene expression in a manner that was inversely correlated to the degree of inflammatory response. In contrast, compounds designed to directly modulate LBD epitopes outside helix-12, led to dissociated levels of GR-mediated gene expression and inflammatory response. Therefore, these new series of compounds and their derivatives will be useful to dissect the ligand-dependent features of GR signaling specificity. 相似文献
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Doubling the size of the glucocorticoid receptor ligand binding pocket by deacylcortivazol
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Suino-Powell K Xu Y Zhang C Tao YG Tolbert WD Simons SS Xu HE 《Molecular and cellular biology》2008,28(6):1915-1923
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. 相似文献
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John L. Gilmore James E. Sheppeck Jim Wang T.G. Murali Dhar Cullen Cavallaro Arthur M. Doweyko Lorraine Mckay Mark D. Cunningham Sium F. Habte Steven G. Nadler John H. Dodd John E. Somerville Joel C. Barrish 《Bioorganic & medicinal chemistry letters》2013,23(19):5448-5451
SAR was used to further develop an indazole class of non-steroidal glucocorticoid receptor agonists aided by a GR LBD (ligand-binding domain)-agonist co-crystal structure described in the accompanying paper. Progress towards discovering a dissociated GR agonist guided by human in vitro assays biased the optimization of this compound series towards partial agonists that possessed excellent selectivity against other nuclear hormone receptors. 相似文献