4TW8

The Fk1-Fk2 domains of FKBP52 in complex with iFit-FL

Summary for 4TW8

• Entry DOI: 10.2210/pdb4tw8/pdb
• Descriptor: Peptidyl-prolyl cis-trans isomerase FKBP4, 2-(5-{[({3-[(1R)-1-[({(2S)-1-[(2S)-2-[(1S)-cyclohex-2-en-1-yl]-2-(3,4,5-trimethoxyphenyl)acetyl]piperidin-2-yl}carbonyl)oxy]-3-(3,4-dimethoxyphenyl)propyl]phenoxy}acetyl)amino]methyl}-6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid (3 entities in total)
• Functional Keywords: fk-506 binding domain, hsp90 cochaperone, immunophiline, peptidyl-prolyl isomerase, ligand selectivity, isomerase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm, cytosol : Q02790
• Total number of polymer chains: 2
• Total formula weight: 55118.41

Authors

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. (deposition date: 2014-06-30, release date: 2014-11-26, Last modification date: 2023-12-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (3.003 Å)