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PDBsum entry 4tw7
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References listed in PDB file
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Key reference
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Title
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Selective inhibitors of the fk506-Binding protein 51 by induced fit.
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Authors
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S.Gaali,
A.Kirschner,
S.Cuboni,
J.Hartmann,
C.Kozany,
G.Balsevich,
C.Namendorf,
P.Fernandez-Vizarra,
C.Sippel,
A.S.Zannas,
R.Draenert,
E.B.Binder,
O.F.Almeida,
G.Rühter,
M.Uhr,
M.V.Schmidt,
C.Touma,
A.Bracher,
F.Hausch.
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Ref.
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Nat Chem Biol, 2015,
11,
33-37.
[DOI no: ]
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PubMed id
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Abstract
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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.
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Secondary reference #1
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Title
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Structural characterization of the ppiase domain of fkbp51, A cochaperone of human hsp90.
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Authors
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A.Bracher,
C.Kozany,
A.K.Thost,
F.Hausch.
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Ref.
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Acta Crystallogr D Biol Crystallogr, 2011,
67,
549-559.
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PubMed id
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