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PDBsum entry 2ooh

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protein ligands Protein-protein interface(s) links
Isomerase PDB id
2ooh
Jmol
Contents
Protein chains
114 a.a. *
Ligands
SO4 ×8
OX3 ×2
GOL ×2
Waters ×305
* Residue conservation analysis
PDB id:
2ooh
Name: Isomerase
Title: Crystal structure of mif bound to a novel inhibitor, oxim-11
Structure: Macrophage migration inhibitory factor. Chain: a, b, c. Synonym: mif, phenylpyruvate tautomerase, glycosylation-inh factor, gif, (ec 5.3.2.1). Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: mif. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Resolution:
1.85Å     R-factor:   0.191     R-free:   0.218
Authors: G.V.Crichlow,Y.Al-Abed,E.Lolis
Key ref:
G.V.Crichlow et al. (2007). Alternative chemical modifications reverse the binding orientation of a pharmacophore scaffold in the active site of macrophage migration inhibitory factor. J Biol Chem, 282, 23089-23095. PubMed id: 17526494 DOI: 10.1074/jbc.M701825200
Date:
25-Jan-07     Release date:   05-Jun-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P14174  (MIF_HUMAN) -  Macrophage migration inhibitory factor
Seq:
Struc:
115 a.a.
114 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class 2: E.C.5.3.2.1  - Phenylpyruvate tautomerase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Keto-phenylpyruvate = enol-phenylpyruvate
Keto-phenylpyruvate
Bound ligand (Het Group name = OX3)
matches with 42.86% similarity
= enol-phenylpyruvate
   Enzyme class 3: E.C.5.3.3.12  - L-dopachrome isomerase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway:
      Reaction: L-dopachrome = 5,6-dihydroxyindole-2-carboxylate
L-dopachrome
= 5,6-dihydroxyindole-2-carboxylate
      Cofactor: Zn(2+)
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.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   5 terms 
  Biological process     immune system process   37 terms 
  Biochemical function     chemoattractant activity     8 terms  

 

 
    reference    
 
 
DOI no: 10.1074/jbc.M701825200 J Biol Chem 282:23089-23095 (2007)
PubMed id: 17526494  
 
 
Alternative chemical modifications reverse the binding orientation of a pharmacophore scaffold in the active site of macrophage migration inhibitory factor.
G.V.Crichlow, K.F.Cheng, D.Dabideen, M.Ochani, B.Aljabari, V.A.Pavlov, E.J.Miller, E.Lolis, Y.Al-Abed.
 
  ABSTRACT  
 
Pharmacophores are chemical scaffolds upon which changes in chemical moieties (R-groups) at specific sites are made to identify a combination of R-groups that increases the therapeutic potency of a small molecule inhibitor while minimizing adverse effects. We developed a pharmacophore based on a carbonyloxime (OXIM) scaffold for macrophage migration inhibitory factor (MIF), a protein involved in the pathology of sepsis, to validate that inhibition of a catalytic site could produce therapeutic benefits. We studied the crystal structures of MIF.OXIM-based inhibitors and found two opposite orientations for binding to the active site that were dependent on the chemical structures of an R-group. One orientation was completely unexpected based on previous studies with hydroxyphenylpyruvate and (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1). We further confirmed that the unexpected binding mode targets MIF in cellular studies by showing that one compound, OXIM-11, abolished the counter-regulatory activity of MIF on anti-inflammatory glucocorticoid action. OXIM-11 treatment of mice, initiated 24 h after the onset of cecal ligation and puncture-induced sepsis, significantly improved survival when compared with vehicle-treated controls, confirming that inhibition of the MIF catalytic site could produce therapeutic effects. The crystal structures of the MIF inhibitor complexes provide insight for further structure-based drug design efforts.
 
  Selected figure(s)  
 
Figure 1.
FIGURE 1. Design of MIF inhibitor. Above, MIF tautomerizes dopachrome methyl esters. Below, the structure of (E)-4-hydroxybenzaldehyde O-carbonyloxime scaffold as a novel and potent inhibitor of MIF.
Figure 2.
FIGURE 2. Structure of the MIF/OXIM-scaffold complexes. a and b, stereo views of OXIM-11 (a) and OXIM-6 (b), shown in [A] weighted F[o]–F[c] electron density maps, calculated omitting all inhibitor molecules. The maps are contoured at 3.5 . The figures were prepared using Molscript (29) and Bobscript (26). c, diagrams displaying hydrogen-bond interactions between MIF and OXIM-11 (left) and between MIF and OXIM-6 (right). The neopentyl R-group, which extends out of the active site, is not clearly visible in the electron density and was omitted from the model. For clarity, it is shown in panels b and c in a possible orientation. Panel c was made using ChemDraw.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2007, 282, 23089-23095) copyright 2007.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21547664 D.S.Im (2011).
A promising anti-inflammatory and anti-thrombotic drug for sepsis treatment.
  Arch Pharm Res, 34, 339-342.  
20169062 W.J.Wiersinga, T.Calandra, L.M.Kager, G.J.van der Windt, T.Roger, D.le Roy, S.Florquin, S.J.Peacock, F.C.Sweep, and T.van der Poll (2010).
Expression and function of macrophage migration inhibitory factor (MIF) in melioidosis.
  PLoS Negl Trop Dis, 4, e605.  
20534506 Y.Cho, G.V.Crichlow, J.J.Vermeire, L.Leng, X.Du, M.E.Hodsdon, R.Bucala, M.Cappello, M.Gross, F.Gaeta, K.Johnson, and E.J.Lolis (2010).
Allosteric inhibition of macrophage migration inhibitory factor revealed by ibudilast.
  Proc Natl Acad Sci U S A, 107, 11313-11318.
PDB codes: 3ijg 3ijj
19090677 G.V.Crichlow, J.B.Lubetsky, L.Leng, R.Bucala, and E.J.Lolis (2009).
Structural and kinetic analyses of macrophage migration inhibitory factor active site interactions.
  Biochemistry, 48, 132-139.
PDB codes: 3ce4 3djh 3dji
19827093 S.E.Dobson, K.D.Augustijn, J.A.Brannigan, C.Schnick, C.J.Janse, E.J.Dodson, A.P.Waters, and A.J.Wilkinson (2009).
The crystal structures of macrophage migration inhibitory factor from Plasmodium falciparum and Plasmodium berghei.
  Protein Sci, 18, 2578-2591.
PDB codes: 2wkb 2wkf
18721909 S.Stosic-Grujicic, I.Stojanovic, and F.Nicoletti (2009).
MIF in autoimmunity and novel therapeutic approaches.
  Autoimmun Rev, 8, 244-249.  
18794110 M.Winner, J.Meier, S.Zierow, B.E.Rendon, G.V.Crichlow, R.Riggs, R.Bucala, L.Leng, N.Smith, E.Lolis, J.O.Trent, and R.A.Mitchell (2008).
A novel, macrophage migration inhibitory factor suicide substrate inhibits motility and growth of lung cancer cells.
  Cancer Res, 68, 7253-7257.
PDB code: 3b9s
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.