5UFS

X-Ray Crystal Structure of the Ancestral Glucocorticoid Receptor 2 ligand binding domain in complex with triamcinolone acetonide and SHP coregulator fragment

5UFS の概要

• エントリーDOI: 10.2210/pdb5ufs/pdb
• 分子名称: Ancestral Glucocorticoid Receptor2, SHP NR Box 1 Peptide, Triamcinolone acetonide, ... (4 entities in total)
• 機能のキーワード: nuclear receptors, glucocorticoid receptor, ligand binding domain, hormone receptor
• 由来する生物種: unidentified; 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 60252.18

構造登録者

Weikum, E.R.,Ortlund, E.A. (登録日: 2017-01-05, 公開日: 2017-04-26, 最終更新日: 2023-10-04)

主引用文献

Weikum, E.R.,Okafor, C.D.,D'Agostino, E.H.,Colucci, J.K.,Ortlund, E.A.
Structural Analysis of the Glucocorticoid Receptor Ligand-Binding Domain in Complex with Triamcinolone Acetonide and a Fragment of the Atypical Coregulator, Small Heterodimer Partner.
Mol. Pharmacol., 92:12-21, 2017

PubMed Abstract: The synthetic glucocorticoids (GCs) dexamethasone, mometasone furoate, and triamcinolone acetonide are pharmaceutical mainstays to treat chronic inflammatory diseases. These drugs bind to the glucocorticoid receptor (GR), a ligand-activated transcription factor and member of the nuclear receptor superfamily. The GR is widely recognized as a therapeutic target for its ability to counter proinflammatory signaling. Despite the popularity of GCs in the clinic, long-term use leads to numerous side effects, driving the need for new and improved drugs with less off-target pharmacology. X-ray crystal structures have played an important role in the drug-design process, permitting the characterization of robust structure-function relationships. However, steroid receptor ligand-binding domains (LBDs) are inherently unstable, and their crystallization requires extensive mutagenesis to enhance expression and crystallization. Here, we use an ancestral variant of GR as a tool to generate a high-resolution crystal structure of GR in complex with the potent glucocorticoid triamcinolone acetonide (TA) and a fragment of the small heterodimer partner (SHP). Using structural analysis, molecular dynamics, and biochemistry, we show that TA increases intramolecular contacts within the LBD to drive affinity and enhance stability of the receptor-ligand complex. These data support the emerging theme that ligand-induced receptor conformational dynamics at the mouth of the pocket play a major role in steroid receptor activation. This work also represents the first GR structure in complex with SHP, which has been suggested to play a role in modulating hepatic GR function.

PubMed: 28396564
DOI: 10.1124/mol.117.108506

実験手法

X-RAY DIFFRACTION (2.118 Å)