Alternative dimerization interfaces in the glucocorticoid receptor-α ligand binding domain
Alternative dimerization interfaces in the glucocorticoid receptor-α ligand binding domain
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DOI：
10.1016/j.bbagen.2018.04.022
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发表时间：
2018-08-01
影响因子：
3
通讯作者：
Dejaegere, Annick
中科院分区：
文献类型：
--
作者：
Bianchetti, Laurent;Wassmer, Bianca;Dejaegere, Annick
背景：核激素受体（NR）构成一个多域配体激活转录因子大家族。二聚化对其调节至关重要，DNA 结合域 (DBD) 和配体结合域 (LBD) 都参与二聚化。有趣的是，糖皮质激素受体-α (GR α) 呈现出与同源雌激素受体-α (ER α) 相似的 DBD 二聚体结构，但 LBD 呈现非典型二聚体结构。所提出的 GR α LBD 二聚体的生理相关性是一个有争议的话题。方法：我们使用基于 PISA 和 MM/PBSA 方法的能量分析以及序列保守分析，使用 ER α LBD 二聚体作为参考点，分析了晶体中观察到的所有 GR α LBD 同二聚体。结果：观察到 GR α LBD 的几个二聚体组装体。通常认为与生理相关的组装显示出弱的结合自由能并且在接触界面处没有显着的残基保守性，而由螺旋9和C端残基介导的替代同二聚体显示出显着的结合自由能和残基保守性。然而，晶体中发现的 GR α LBD 组装体都不像典型的 ER α LBD 二聚体那样稳定或保守。 GR α C 末端序列（F 结构域）对所有可用结构中的规范二聚体组装形成空间障碍。结论：我们的分析要求重新检查当前接受的 GR α 同二聚体结构并对替代架构进行实验研究。一般意义：这项工作质疑当前接受的架构的有效性。这对于解释生理数据和与糖皮质激素研究有关的治疗设计具有影响。
Background: Nuclear hormone receptors (NRs) constitute a large family of multi-domain ligand-activated transcription factors. Dimerization is essential for their regulation, and both DNA binding domain (DBD) and ligand binding domain (LBD) are implicated in dimerization. Intriguingly, the glucocorticoid receptor-alpha (GR alpha) presents a DBD dimeric architecture similar to that of the homologous estrogen receptor-alpha (ER alpha), but an atypical dimeric architecture for the LBD. The physiological relevance of the proposed GR alpha LBD dimer is a subject of debate.Methods: We analyzed all GR alpha LBD homodimers observed in crystals using an energetic analysis based on the PISA and on the MM/PBSA methods and a sequence conservation analysis, using the ER alpha LBD dimer as a reference point.Results: Several dimeric assemblies were observed for GR alpha LBD. The assembly generally taken to be physiologically relevant showed weak binding free energy and no significant residue conservation at the contact interface, while an alternative homodimer mediated by both helix 9 and C-terminal residues showed significant binding free energy and residue conservation. However, none of the GR alpha LBD assemblies found in crystals are as stable or conserved as the canonical ER alpha LBD dimer. GR alpha C-terminal sequence (F-domain) forms a steric obstacle to the canonical dimer assembly in all available structures.Conclusions: Our analysis calls for a re-examination of the currently accepted GR alpha homodimer structure and experimental investigations of the alternative architectures.General significance: This work questions the validity of the currently accepted architecture. This has implications for interpreting physiological data and for therapeutic design pertaining to glucocorticoid research.