4TW6

The Fk1 domain of FKBP51 in complex with iFit1

4TW6 の概要

• エントリーDOI: 10.2210/pdb4tw6/pdb
• 分子名称: Peptidyl-prolyl cis-trans isomerase FKBP5, (3-{(1R)-3-(3,4-dimethoxyphenyl)-1-[({(2S)-1-[(2S)-2-(3,4,5-trimethoxyphenyl)pent-4-enoyl]piperidin-2-yl}carbonyl)oxy]propyl}phenoxy)acetic acid, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: fk-506 binding domain, hsp90 cochaperone, immunophiline, peptidyl-prolyl isomerase, ligand selectivity, isomerase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm: Q13451
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 14846.95

構造登録者

Gaali, S.,Kirschner, A.,Cuboni, S.,Hartmann, J.,Kozany, C.,Balsevich, G.,Namendorf, C.,Fernandez-Vizarra, P.,Almeida, O.F.X.,Ruehter, G.,Uhr, M.,Schmidt, M.V.,Touma, C.,Bracher, A.,Hausch, F. (登録日: 2014-06-30, 公開日: 2014-11-26, 最終更新日: 2023-12-20)

主引用文献

Gaali, S.,Kirschner, A.,Cuboni, S.,Hartmann, J.,Kozany, C.,Balsevich, G.,Namendorf, C.,Fernandez-Vizarra, P.,Sippel, C.,Zannas, A.S.,Draenert, R.,Binder, E.B.,Almeida, O.F.,Ruhter, G.,Uhr, M.,Schmidt, M.V.,Touma, C.,Bracher, A.,Hausch, F.
Selective inhibitors of the FK506-binding protein 51 by induced fit.
Nat.Chem.Biol., 11:33-37, 2015

PubMed Abstract: The FK506-binding protein 51 (FKBP51, encoded by the FKBP5 gene) is an established risk factor for stress-related psychiatric disorders such as major depression. Drug discovery for FKBP51 has been hampered by the inability to pharmacologically differentiate against the structurally similar but functional opposing homolog FKBP52, and all known FKBP ligands are unselective. Here, we report the discovery of the potent and highly selective inhibitors of FKBP51, SAFit1 and SAFit2. This new class of ligands achieves selectivity for FKBP51 by an induced-fit mechanism that is much less favorable for FKBP52. By using these ligands, we demonstrate that selective inhibition of FKBP51 enhances neurite elongation in neuronal cultures and improves neuroendocrine feedback and stress-coping behavior in mice. Our findings provide the structural and functional basis for the development of mechanistically new antidepressants.

PubMed: 25436518
DOI: 10.1038/nchembio.1699

実験手法

X-RAY DIFFRACTION (1.4 Å)