2ooz
From Proteopedia
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| - | [[Image:2ooz.jpg|left|200px]] | + | [[Image:2ooz.jpg|left|200px]] |
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| - | '''Macrophage Migration Inhibitory Factor (MIF) Complexed with OXIM6 (an OXIM Derivative Not Containing a Ring in its R-group)''' | + | {{Structure |
| + | |PDB= 2ooz |SIZE=350|CAPTION= <scene name='initialview01'>2ooz</scene>, resolution 1.8Å | ||
| + | |SITE= <scene name='pdbsite=AC1:So4+Binding+Site+For+Residue+A+901'>AC1</scene>, <scene name='pdbsite=AC2:So4+Binding+Site+For+Residue+B+902'>AC2</scene>, <scene name='pdbsite=AC3:So4+Binding+Site+For+Residue+C+903'>AC3</scene>, <scene name='pdbsite=AC4:So4+Binding+Site+For+Residue+A+904'>AC4</scene>, <scene name='pdbsite=AC5:So4+Binding+Site+For+Residue+B+905'>AC5</scene>, <scene name='pdbsite=AC6:Ox5+Binding+Site+For+Residue+A+200'>AC6</scene>, <scene name='pdbsite=AC7:Ox5+Binding+Site+For+Residue+B+200'>AC7</scene>, <scene name='pdbsite=AC8:Gol+Binding+Site+For+Residue+A+701'>AC8</scene>, <scene name='pdbsite=AC9:Gol+Binding+Site+For+Residue+B+702'>AC9</scene>, <scene name='pdbsite=BC1:Gol+Binding+Site+For+Residue+C+703'>BC1</scene> and <scene name='pdbsite=BC2:Ipa+Binding+Site+For+Residue+A+801'>BC2</scene> | ||
| + | |LIGAND= <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=OX5:4-HYDROXYBENZALDEHYDE+O-(3,3-DIMETHYLBUTANOYL)OXIME'>OX5</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene> and <scene name='pdbligand=IPA:ISOPROPYL ALCOHOL'>IPA</scene> | ||
| + | |ACTIVITY= [http://en.wikipedia.org/wiki/Phenylpyruvate_tautomerase Phenylpyruvate tautomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.3.2.1 5.3.2.1] | ||
| + | |GENE= MIF ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | }} | ||
| + | |||
| + | '''Macrophage Migration Inhibitory Factor (MIF) Complexed with OXIM6 (an OXIM Derivative Not Containing a Ring in its R-group)''' | ||
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==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 2OOZ is a [ | + | 2OOZ is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2OOZ OCA]. |
==Reference== | ==Reference== | ||
| - | Alternative chemical modifications reverse the binding orientation of a pharmacophore scaffold in the active site of macrophage migration inhibitory factor., Crichlow GV, Cheng KF, Dabideen D, Ochani M, Aljabari B, Pavlov VA, Miller EJ, Lolis E, Al-Abed Y, J Biol Chem. 2007 Aug 10;282(32):23089-95. Epub 2007 May 25. PMID:[http:// | + | Alternative chemical modifications reverse the binding orientation of a pharmacophore scaffold in the active site of macrophage migration inhibitory factor., Crichlow GV, Cheng KF, Dabideen D, Ochani M, Aljabari B, Pavlov VA, Miller EJ, Lolis E, Al-Abed Y, J Biol Chem. 2007 Aug 10;282(32):23089-95. Epub 2007 May 25. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17526494 17526494] |
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Phenylpyruvate tautomerase]] | [[Category: Phenylpyruvate tautomerase]] | ||
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[[Category: OX5]] | [[Category: OX5]] | ||
[[Category: SO4]] | [[Category: SO4]] | ||
| - | [[Category: alternative ligand-binding | + | [[Category: alternative ligand-binding mode]] |
[[Category: isomerase]] | [[Category: isomerase]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 18:02:34 2008'' |
Revision as of 16:02, 20 March 2008
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| , resolution 1.8Å | |||||||
|---|---|---|---|---|---|---|---|
| Sites: | , , , , , , , , , and | ||||||
| Ligands: | , , and | ||||||
| Gene: | MIF (Homo sapiens) | ||||||
| Activity: | Phenylpyruvate tautomerase, with EC number 5.3.2.1 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Macrophage Migration Inhibitory Factor (MIF) Complexed with OXIM6 (an OXIM Derivative Not Containing a Ring in its R-group)
Contents |
Overview
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.
Disease
Known diseases associated with this structure: Persistent Mullerian duct syndrome, type I OMIM:[600957], Rheumatoid arthritis, systemic juvenile, susceptibility to OMIM:[153620]
About this Structure
2OOZ is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Alternative chemical modifications reverse the binding orientation of a pharmacophore scaffold in the active site of macrophage migration inhibitory factor., Crichlow GV, Cheng KF, Dabideen D, Ochani M, Aljabari B, Pavlov VA, Miller EJ, Lolis E, Al-Abed Y, J Biol Chem. 2007 Aug 10;282(32):23089-95. Epub 2007 May 25. PMID:17526494
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