2ooz
From Proteopedia
| Line 4: | Line 4: | ||
|PDB= 2ooz |SIZE=350|CAPTION= <scene name='initialview01'>2ooz</scene>, resolution 1.8Å | |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> | |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= | + | |LIGAND= <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene>, <scene name='pdbligand=OX5:4-HYDROXYBENZALDEHYDE+O-(3,3-DIMETHYLBUTANOYL)OXIME'>OX5</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene> |
| - | + | |ACTIVITY= <span class='plainlinks'>[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] </span> | |
|GENE= MIF ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |GENE= MIF ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[2ooh|2OOH]], [[2oow|2OOW]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2ooz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ooz OCA], [http://www.ebi.ac.uk/pdbsum/2ooz PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2ooz RCSB]</span> | ||
}} | }} | ||
| Line 16: | Line 19: | ||
==Disease== | ==Disease== | ||
| - | Known | + | Known disease associated with this structure: Persistent Mullerian duct syndrome, type I OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600957 600957]], Rheumatoid arthritis, systemic juvenile, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=153620 153620]] |
==About this Structure== | ==About this Structure== | ||
| Line 29: | Line 32: | ||
[[Category: Crichlow, G V.]] | [[Category: Crichlow, G V.]] | ||
[[Category: Lolis, E.]] | [[Category: Lolis, E.]] | ||
| - | [[Category: GOL]] | ||
| - | [[Category: IPA]] | ||
| - | [[Category: OX5]] | ||
| - | [[Category: SO4]] | ||
[[Category: alternative ligand-binding mode]] | [[Category: alternative ligand-binding mode]] | ||
[[Category: isomerase]] | [[Category: isomerase]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 04:20:59 2008'' |
Revision as of 01:21, 31 March 2008
| |||||||
| , resolution 1.8Å | |||||||
|---|---|---|---|---|---|---|---|
| Sites: | , , , , , , , , , and | ||||||
| Ligands: | , , , | ||||||
| Gene: | MIF (Homo sapiens) | ||||||
| Activity: | Phenylpyruvate tautomerase, with EC number 5.3.2.1 | ||||||
| Related: | 2OOH, 2OOW
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| 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 disease 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
Page seeded by OCA on Mon Mar 31 04:20:59 2008
