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2ooh

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[[Image:2ooh.jpg|left|200px]]
[[Image:2ooh.jpg|left|200px]]
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{{Structure
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<!--
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|PDB= 2ooh |SIZE=350|CAPTION= <scene name='initialview01'>2ooh</scene>, resolution 1.85&Aring;
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The line below this paragraph, containing "STRUCTURE_2ooh", creates the "Structure Box" on the page.
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|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+B+904'>AC4</scene>, <scene name='pdbsite=AC5:So4+Binding+Site+For+Residue+A+905'>AC5</scene>, <scene name='pdbsite=AC6:So4+Binding+Site+For+Residue+A+906'>AC6</scene>, <scene name='pdbsite=AC7:So4+Binding+Site+For+Residue+A+907'>AC7</scene>, <scene name='pdbsite=AC8:So4+Binding+Site+For+Residue+A+908'>AC8</scene>, <scene name='pdbsite=AC9:Ox3+Binding+Site+For+Residue+B+200'>AC9</scene>, <scene name='pdbsite=BC1:Ox3+Binding+Site+For+Residue+C+200'>BC1</scene>, <scene name='pdbsite=BC2:Gol+Binding+Site+For+Residue+C+701'>BC2</scene> and <scene name='pdbsite=BC3:Gol+Binding+Site+For+Residue+C+702'>BC3</scene>
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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|LIGAND= <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=OX3:4-HYDROXYBENZALDEHYDE+O-(CYCLOHEXYLCARBONYL)OXIME'>OX3</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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|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>
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or leave the SCENE parameter empty for the default display.
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|GENE= MIF ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
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-->
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|DOMAIN=
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{{STRUCTURE_2ooh| PDB=2ooh | SCENE= }}
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|RELATEDENTRY=[[2oow|2OOW]], [[2ooz|2OOZ]]
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2ooh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ooh OCA], [http://www.ebi.ac.uk/pdbsum/2ooh PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2ooh RCSB]</span>
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}}
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'''Crystal Structure of MIF bound to a Novel Inhibitor, OXIM-11'''
'''Crystal Structure of MIF bound to a Novel Inhibitor, OXIM-11'''
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[[Category: Crichlow, G V.]]
[[Category: Crichlow, G V.]]
[[Category: Lolis, E.]]
[[Category: Lolis, E.]]
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[[Category: alternative ligand-binding mode]]
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[[Category: Alternative ligand-binding mode]]
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[[Category: isomerase]]
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[[Category: Isomerase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 11:19:49 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 04:20:51 2008''
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Revision as of 08:19, 4 May 2008

Image:2ooh.jpg

Template:STRUCTURE 2ooh

Crystal Structure of MIF bound to a Novel Inhibitor, OXIM-11


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

2OOH 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 Sun May 4 11:19:49 2008

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