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PDBsum entry 6cbh
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PDB id:
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Cytokine
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Title:
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Macrophage migration inhibitory factor in complex with a pyrazole inhibitor (8m)
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Structure:
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Macrophage migration inhibitory factor. Chain: a, b, c. Synonym: mif,glycosylation-inhibiting factor,gif,l-dopachrome isomerase,l-dopachrome tautomerase,phenylpyruvate tautomerase. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: mif, glif, mmif. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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2.00Å
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R-factor:
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0.177
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R-free:
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0.214
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Authors:
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M.J.Robertson,S.G.Krimmer,W.L.Jorgensen
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Key ref:
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V.Trivedi-Parmar
et al.
(2018).
Optimization of Pyrazoles as Phenol Surrogates to Yield Potent Inhibitors of Macrophage Migration Inhibitory Factor.
ChemMedChem,
13,
1092-1097.
PubMed id:
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Date:
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02-Feb-18
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Release date:
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04-Apr-18
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PROCHECK
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Headers
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References
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P14174
(MIF_HUMAN) -
Macrophage migration inhibitory factor from Homo sapiens
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Seq:
Struc:
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115 a.a.
114 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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Enzyme class 2:
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E.C.5.3.2.1
- phenylpyruvate tautomerase.
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Reaction:
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3-phenylpyruvate = enol-phenylpyruvate
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3-phenylpyruvate
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=
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enol-phenylpyruvate
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Enzyme class 3:
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E.C.5.3.3.12
- L-dopachrome isomerase.
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Pathway:
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Reaction:
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L-dopachrome = 5,6-dihydroxyindole-2-carboxylate
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L-dopachrome
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=
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5,6-dihydroxyindole-2-carboxylate
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Cofactor:
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Zn(2+)
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Note, where more than one E.C. class is given (as above), each may
correspond to a different protein domain or, in the case of polyprotein
precursors, to a different mature protein.
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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ChemMedChem
13:1092-1097
(2018)
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PubMed id:
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Optimization of Pyrazoles as Phenol Surrogates to Yield Potent Inhibitors of Macrophage Migration Inhibitory Factor.
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V.Trivedi-Parmar,
M.J.Robertson,
J.A.Cisneros,
S.G.Krimmer,
W.L.Jorgensen.
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ABSTRACT
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Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that
is implicated in the regulation of inflammation, cell proliferation, and
neurological disorders. MIF is also an enzyme that functions as a keto-enol
tautomerase. Most potent MIF tautomerase inhibitors incorporate a phenol, which
hydrogen bonds to Asn97 in the active site. Starting from a 113-μm docking hit,
we report results of structure-based and computer-aided design that have
provided substituted pyrazoles as phenol alternatives with potencies of
60-70 nm. Crystal structures of complexes of MIF with the pyrazoles highlight
the contributions of hydrogen bonding with Lys32 and Asn97, and aryl-aryl
interactions with Tyr36, Tyr95, and Phe113 to the binding.
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