Selective inhibitors of the FK506-binding protein 51 by induced fit
| Autor: | Paula Fernandez-Vizarra, Gerd Ruhter, Serena Cuboni, Mathias V. Schmidt, S. Gaali, Alexander Kirschner, Felix Hausch, Georgia Balsevich, Elisabeth B. Binder, Anthony S. Zannas, Andreas Bracher, Christian Namendorf, Chadi Touma, Christian Kozany, Rika Draenert, Osborne F. X. Almeida, Manfred Uhr, Jakob Hartmann, Claudia Sippel |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Conformational change Protein Conformation Stereochemistry Isomerase Biology Tacrolimus Binding Proteins Mice Adaptation Psychological Drug Discovery Neurites Animals Humans skin and connective tissue diseases Molecular Biology Cells Cultured Binding Sites Behavior Animal Mechanism (biology) Cell Biology FKBP52 Antidepressive Agents Mice Inbred C57BL FKBP Mutation sense organs |
| Zdroj: | Nature Chemical Biology. 11:33-37 |
| ISSN: | 1552-4469 1552-4450 |
| DOI: | 10.1038/nchembio.1699 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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