2ooz

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spinqualitylabelsall models 2ooz, resolution 1.8Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Macrophage Migration Inhibitory Factor (MIF) Complexed with OXIM6 (an OXIM Derivative Not Containing a Ring in its R-group)

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

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 24h after the onset of cecal, ligation and puncture-induced sepsis, significantly improved survival, compared to 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 with SO4, OX5, GOL and IPA as ligands. Active as Phenylpyruvate tautomerase, with EC number 5.3.2.1 Full crystallographic information is available from OCA.

Reference

Alternative chemical modifications reverse the binding orientation of a pharmacophore scaffold in the active site of MIF., Crichlow GV, Cheng KF, Dabideen D, Ochani M, Aljabari B, Pavlov VA, Miller EJ, Lolis E, Al-Abed Y, J Biol Chem. 2007 May 25;. PMID:17526494

Page seeded by OCA on Mon Nov 12 23:14:26 2007