4k9g
From Proteopedia
(Difference between revisions)
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| - | ''' | + | ==1.55 A Crystal Structure of Macrophage Migration Inhibitory Factor bound to ISO-66 and a related compound== |
| + | <StructureSection load='4k9g' size='340' side='right' caption='[[4k9g]], [[Resolution|resolution]] 1.55Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[4k9g]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4K9G OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4K9G FirstGlance]. <br> | ||
| + | </td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1Q1:1-[(5S)-3-(3-FLUORO-4-HYDROXYPHENYL)-4,5-DIHYDRO-1,2-OXAZOL-5-YL]PROPAN-2-ONE'>1Q1</scene>, <scene name='pdbligand=1Q2:(4R,6Z)-6-(3-FLUORO-4-HYDROXYPHENYL)-4-HYDROXY-6-IMINOHEXAN-2-ONE'>1Q2</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene><br> | ||
| + | <tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1ljt|1ljt]]</td></tr> | ||
| + | <tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4k9g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4k9g OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4k9g RCSB], [http://www.ebi.ac.uk/pdbsum/4k9g PDBsum]</span></td></tr> | ||
| + | <table> | ||
| + | == Disease == | ||
| + | [[http://www.uniprot.org/uniprot/MIF_HUMAN MIF_HUMAN]] Genetic variations in MIF are associated with susceptibility to rheumatoid arthritis systemic juvenile (RASJ) [MIM:[http://omim.org/entry/604302 604302]]. An inflammatory articular disorder with systemic-onset beginning before the age of 16. It represents a subgroup of juvenile arthritis associated with severe extraarticular features and occasionally fatal complications. During active phases of the disorder, patients display a typical daily spiking fever, an evanescent macular rash, lymphadenopathy, hepatosplenomegaly, serositis, myalgia and arthritis. | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/MIF_HUMAN MIF_HUMAN]] Pro-inflammatory cytokine. Involved in the innate immune response to bacterial pathogens. The expression of MIF at sites of inflammation suggests a role as mediator in regulating the function of macrophages in host defense. Counteracts the anti-inflammatory activity of glucocorticoids. Has phenylpyruvate tautomerase and dopachrome tautomerase activity (in vitro), but the physiological substrate is not known. It is not clear whether the tautomerase activity has any physiological relevance, and whether it is important for cytokine activity.<ref>PMID:15908412</ref> <ref>PMID:17443469</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Macrophage migration inhibitory factor (MIF) is a pleiotropic pro-inflammatory cytokine, which possesses a contributing role in cancer progression and metastasis and, thus, is now considered a promising anticancer drug target. Many MIF-inactivating strategies have proven successful in delaying cancer growth. Here, we report on the synthesis of ISO-66, a novel, highly stable, small-molecule MIF inhibitor, an analog of ISO-1 with improved characteristics. The MIF:ISO-66 co-crystal structure demonstrated that ISO-66 ligates the tautomerase active site of MIF, which has previously been shown to play an important role in its biological functions. In vitro, ISO-66 enhanced specific and non-specific anticancer immune responses, whereas prolonged administration of ISO-66 in mice with established syngeneic melanoma or colon cancer was non-toxic and resulted in a significant decrease in tumor burden. Subsequent ex vivo analysis of mouse splenocytes revealed that the observed decrease in tumor growth rates was likely mediated by the selective in vivo expansion of antitumor-reactive effector cells induced by ISO-66. Compared to other MIF-inactivating strategies employed in vivo, the anticancer activity of ISO-66 is demonstrated to be of equal or better efficacy. Our findings suggest that targeting MIF, via highly specific and stable compounds, such as ISO-66, may be effective for cancer treatment and stimulation of anticancer immune responses. | ||
| - | + | ISO-66, a novel inhibitor of macrophage migration, shows efficacy in melanoma and colon cancer models.,Ioannou K, Cheng KF, Crichlow GV, Birmpilis AI, Lolis EJ, Tsitsilonis OE, Al-Abed Y Int J Oncol. 2014 Oct;45(4):1457-68. doi: 10.3892/ijo.2014.2551. Epub 2014 Jul, 22. PMID:25050663<ref>PMID:25050663</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | == References == | |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Al-Abed, Y.]] | ||
| + | [[Category: Crichlow, G V.]] | ||
| + | [[Category: Lolis, E J.]] | ||
| + | [[Category: Cytokine]] | ||
| + | [[Category: Isomerase]] | ||
| + | [[Category: Secreted/endocytosed]] | ||
Revision as of 10:18, 24 September 2014
1.55 A Crystal Structure of Macrophage Migration Inhibitory Factor bound to ISO-66 and a related compound
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