期刊
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
卷 1862, 期 8, 页码 1810-1825出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbagen.2018.04.022
关键词
Glucocorticoid receptor; Ligand binding domain; Homodimer; Binding free energy; Sequence conservation; Molecular modeling
资金
- French National Institute of Health and Medical Research (INSERM)
- French National Center for Scientific Research (CNRS)
- Strasbourg University (UdS)
- Agence Nationale de la Recherche [ANR-10-LABX-0030-INRT, ANR-10-IDEX-0002-02]
- Labex INRT funds
- Equipex Equip@ Meso project (Programme Investissements d'Avenir)
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.
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