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Conformational changes of the glucocorticoid receptor ligand binding domain induced by ligand and cofactor binding, and the location of cofactor binding sites determined by hydrogen/deuterium exchange mass spectrometry

机译:配体和辅因子结合引起的糖皮质激素受体配体结合域的构象变化,以及氢/氘交换质谱法测定的辅因子结合位点的位置

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摘要

HXMS (hydrogen/deuterium exchange mass spectrometry) of the glucocorticoid receptor ligand-binding domain (GR LBD) complexed with the agonist dexamethasone and the antagonist RU-486 is described. Variations in the rates of exchange were observed in regions consistent with the published crystal structures of GR LBD complexed with RU-486 when compared with the GR dexamethasone complex. We also report the HXMS results for agonist-bound GR LBD with the coactivator transcriptional intermediary factor 2 (TIF2) and anatagonist-bound GR LBD with nuclear receptor corepressor (NCoR). Alterations in exchange rates observed for agonist-bound GR LBD with TIF2 present were consistent with the published crystal structural contacts for the complex. Alterations in exchange rates observed for antagonist-bound GR LBD with NCoR were a subset of those observed with TIF2 binding, suggesting a common or overlapping binding site for coactivator and corepressor.
机译:描述了与激动剂地塞米松和拮抗剂RU-486复合的糖皮质激素受体配体结合域(GR LBD)的HXMS(氢/氘交换质谱)。当与GR地塞米松复合物比较时,在与RU-486复合的GR LBD的已公布晶体结构一致的区域中观察到交换速率的变化。我们还报告了激动剂结合的GR LBD与辅激活因子转录中介因子2(TIF2)和拮抗剂结合的GR LBD与核受体corepressor(NCoR)的HXMS结果。对于存在TIF2的激动剂结合的GR LBD,观察到的汇率变化与该复合物的已公布晶体结构接触相一致。用NCoR观察到的与拮抗剂结合的GR LBD的交换速率变化是观察到的与TIF2结合的交换率的一个子集,表明共激活因子和共加压因子具有共同或重叠的结合位点。

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