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2ooh
From Proteopedia
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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.]] | ||
| - | [[Category: | + | [[Category: Alternative ligand-binding mode]] |
| - | [[Category: | + | [[Category: Isomerase]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 11:19:49 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 08:19, 4 May 2008
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
