2oow: Difference between revisions
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==Overview== | ==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. | 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:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600957 600957]], Rheumatoid arthritis, systemic juvenile, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=153620 153620]] | |||
==About this Structure== | ==About this Structure== | ||
2OOW is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=SO4:'>SO4</scene>, <scene name='pdbligand=OX4:'>OX4</scene>, <scene name='pdbligand=GOL:'>GOL</scene> and <scene name='pdbligand=IPA:'>IPA</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2OOW OCA]. | 2OOW is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=SO4:'>SO4</scene>, <scene name='pdbligand=OX4:'>OX4</scene>, <scene name='pdbligand=GOL:'>GOL</scene> and <scene name='pdbligand=IPA:'>IPA</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Known structural/functional Sites: <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+A+904'>AC4</scene>, <scene name='pdbsite=AC5:So4+Binding+Site+For+Residue+C+905'>AC5</scene>, <scene name='pdbsite=AC6:Ox4+Binding+Site+For+Residue+A+200'>AC6</scene>, <scene name='pdbsite=AC7:Ox4+Binding+Site+For+Residue+C+200'>AC7</scene>, <scene name='pdbsite=AC8:Gol+Binding+Site+For+Residue+A+701'>AC8</scene>, <scene name='pdbsite=AC9:Gol+Binding+Site+For+Residue+B+702'>AC9</scene>, <scene name='pdbsite=BC1:Gol+Binding+Site+For+Residue+C+703'>BC1</scene>, <scene name='pdbsite=BC2:Gol+Binding+Site+For+Residue+A+704'>BC2</scene>, <scene name='pdbsite=BC3:Gol+Binding+Site+For+Residue+C+705'>BC3</scene>, <scene name='pdbsite=BC4:Gol+Binding+Site+For+Residue+A+706'>BC4</scene>, <scene name='pdbsite=BC5:Ipa+Binding+Site+For+Residue+C+801'>BC5</scene>, <scene name='pdbsite=BC6:Ipa+Binding+Site+For+Residue+C+802'>BC6</scene> and <scene name='pdbsite=BC7:Ipa+Binding+Site+For+Residue+C+803'>BC7</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2OOW OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: SO4]] | [[Category: SO4]] | ||
[[Category: alternative ligand-binding modes]] | [[Category: alternative ligand-binding modes]] | ||
[[Category: isomerase]] | |||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Feb 13 08:17:55 2008'' | ||
Revision as of 09:17, 13 February 2008
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MIF Bound to a Fluorinated OXIM Derivative
OverviewOverview
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.
DiseaseDisease
Known diseases associated with this structure: Persistent Mullerian duct syndrome, type I OMIM:[600957], Rheumatoid arthritis, systemic juvenile, susceptibility to OMIM:[153620]
About this StructureAbout this Structure
2OOW is a Single protein structure of sequence from Homo sapiens with , , and as ligands. Active as Phenylpyruvate tautomerase, with EC number 5.3.2.1 Known structural/functional Sites: , , , , , , , , , , , , , , and . Full crystallographic information is available from OCA.
ReferenceReference
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
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