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PDBsum entry 4tw7
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PDB id:
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Isomerase
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Title:
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The fk1 domain of fkbp51 in complex with ifit4
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Structure:
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Peptidyl-prolyl cis-trans isomerase fkbp5. Chain: a. Synonym: ppiase fkbp5,51 kda fk506-binding protein,fkbp-51,54 kda progesterone receptor-associated immunophilin,androgen-regulated protein 6,ff1 antigen,fk506-binding protein 5,fkbp-5,fkbp54,p54, hsp90-binding immunophilin,rotamase. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: fkbp5, aig6, fkbp51. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Expression_system_variant: codon plus ril.
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Resolution:
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1.25Å
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R-factor:
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0.131
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R-free:
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0.174
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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,O.F.X.Almeida,G.Ruehter,M.Uhr, M.V.Schmidt,C.Touma,A.Bracher,F.Hausch
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Key ref:
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S.Gaali
et al.
(2015).
Selective inhibitors of the FK506-binding protein 51 by induced fit.
Nat Chem Biol,
11,
33-37.
PubMed id:
DOI:
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Date:
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30-Jun-14
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Release date:
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26-Nov-14
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PROCHECK
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Headers
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References
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Q13451
(FKBP5_HUMAN) -
Peptidyl-prolyl cis-trans isomerase FKBP5 from Homo sapiens
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Seq:
Struc:
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457 a.a.
128 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 4 residue positions (black
crosses)
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Enzyme class:
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E.C.5.2.1.8
- peptidylprolyl isomerase.
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Reaction:
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[protein]-peptidylproline (omega=180) = [protein]-peptidylproline (omega=0)
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Peptidylproline (omega=180)
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=
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peptidylproline (omega=0)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Nat Chem Biol
11:33-37
(2015)
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PubMed id:
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Selective inhibitors of the FK506-binding protein 51 by induced fit.
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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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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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Links
