4E2J

X-Ray Crystal Structure of the Ancestral Glucocorticoid Receptor 2 ligand binding domain in complex with mometasone furoate and TIF-2 coactivator fragment

4E2J の概要

• エントリーDOI: 10.2210/pdb4e2j/pdb
• 分子名称: Ancestral Glucocorticoid Receptor 2, Nuclear receptor coactivator 2, GLYCEROL, ... (6 entities in total)
• 機能のキーワード: nuclear receptor ligand binding domain, glucocorticoid receptor, steroid binding protein, hormone-hormone activator complex, hormone/hormone activator
• 由来する生物種: synthetic construct; 詳細
• 細胞内の位置: Nucleus: Q15596
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 61751.29

構造登録者

Kohn, J.A.,Deshpande, K.,Ortlund, E.A. (登録日: 2012-03-08, 公開日: 2012-03-28, 最終更新日: 2023-09-13)

主引用文献

Kohn, J.A.,Deshpande, K.,Ortlund, E.A.
Deciphering Modern Glucocorticoid Cross-pharmacology Using Ancestral Corticosteroid Receptors.
J.Biol.Chem., 287:16267-16275, 2012

PubMed Abstract: Steroid receptors (SRs) are the largest family of metazoan transcription factors and control genes involved in development, endocrine signaling, reproduction, immunity, and cancer. The entire hormone receptor system is driven by a molecular switch triggered by the binding of small lipophilic ligands. This makes the SRs ideal pharmaceutical targets, yet even the best clinically approved synthetic steroidal agonists are prone to cross-reactivity and off-target pharmacology. The mechanism underlying this promiscuity is derived from the fact that SRs share common structural features derived from their evolutionary relationship. More often than not, rational attempts to probe SR drug selectivity via mutagenesis fail even when high quality structural and functional data are available due to the fact that important mutations often result in nonfunctional receptors. This highlights the fact that SRs suffer from instability, preventing in-depth mutational analysis and hampering crystallization of key receptor-ligand complexes. We have taken a unique approach to address this problem by using a resurrected ancestral protein to determine the structure of a previously intractable complex and identified the structural mechanisms that confer activation and selectivity for a widely used glucocorticoid, mometasone furoate. Moreover, we have identified a single residue located outside of the ligand-binding pocket that controls mometasone furoate antagonism versus agonism in the human mineralocorticoid receptor.

PubMed: 22437833
DOI: 10.1074/jbc.M112.346411

実験手法

X-RAY DIFFRACTION (2.5 Å)