2OOH

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

Summary for 2OOH

• Entry DOI: 10.2210/pdb2ooh/pdb
• Related: 2OOW 2OOZ
• Descriptor: Macrophage migration inhibitory factor, SULFATE ION, 4-HYDROXYBENZALDEHYDE O-(CYCLOHEXYLCARBONYL)OXIME, ... (5 entities in total)
• Functional Keywords: alternative ligand-binding modes, isomerase
• Biological source: Homo sapiens (human)
• Cellular location: Secreted : P14174
• Total number of polymer chains: 3
• Total formula weight: 38512.44

Authors

Crichlow, G.V.,Al-Abed, Y.,Lolis, E. (deposition date: 2007-01-25, release date: 2007-06-05, Last modification date: 2023-08-30)

Primary citation

Crichlow, G.V.,Cheng, K.F.,Dabideen, D.,Ochani, M.,Aljabari, B.,Pavlov, V.A.,Miller, E.J.,Lolis, E.,Al-Abed, Y.
Alternative chemical modifications reverse the binding orientation of a pharmacophore scaffold in the active site of macrophage migration inhibitory factor.
J.Biol.Chem., 282:23089-23095, 2007

PubMed Abstract: 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.

PubMed: 17526494
DOI: 10.1074/jbc.M701825200

Experimental method

X-RAY DIFFRACTION (1.85 Å)