4tw8
The Fk1-Fk2 domains of FKBP52 in complex with iFit-FL
Structural highlights
FunctionFKBP4_HUMAN Immunophilin protein with PPIase and co-chaperone activities (By similarity). Component of unligated steroid receptors heterocomplexes through interaction with heat-shock protein 90 (HSP90). May play a role in the intracellular trafficking of heterooligomeric forms of steroid hormone receptors between cytoplasm and nuclear compartments (By similarity). The isomerase activity controls neuronal growth cones via regulation of TRPC1 channel opening. Acts also as a regulator of microtubule dynamics by inhibiting MAPT/TAU ability to promote microtubule assembly. May have a protective role against oxidative stress in mitochondria.[1] [2] [3] [4] [5] Publication Abstract from PubMedThe 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. Selective inhibitors of the FK506-binding protein 51 by induced fit.,Gaali S, Kirschner A, Cuboni S, Hartmann J, Kozany C, Balsevich G, Namendorf C, Fernandez-Vizarra P, Sippel C, Zannas AS, Draenert R, Binder EB, Almeida OF, Ruhter G, Uhr M, Schmidt MV, Touma C, Bracher A, Hausch F Nat Chem Biol. 2014 Dec 1. doi: 10.1038/nchembio.1699. PMID:25436518[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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