2oow

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{{STRUCTURE_2oow| PDB=2oow | SCENE= }}
{{STRUCTURE_2oow| PDB=2oow | SCENE= }}
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'''MIF Bound to a Fluorinated OXIM Derivative'''
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===MIF Bound to a Fluorinated OXIM Derivative===
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==Overview==
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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.
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{{ABSTRACT_PUBMED_17526494}}
==Disease==
==Disease==
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[[Category: Alternative ligand-binding mode]]
[[Category: Alternative ligand-binding mode]]
[[Category: Isomerase]]
[[Category: Isomerase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 11:21:26 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 18:19:01 2008''

Revision as of 15:19, 27 July 2008

Image:2oow.png

Template:STRUCTURE 2oow

Contents

MIF Bound to a Fluorinated OXIM Derivative

Template:ABSTRACT PUBMED 17526494

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

2OOW 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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