View source for 5hvs


==Crystal Structure of Macrophage Migration Inhibitory Factor (MIF) with a Biaryltriazole Inhibitor (3i-305)==
<StructureSection load='5hvs' size='340' side='right'caption='[[5hvs]], [[Resolution|resolution]] 1.75&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5hvs]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HVS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5HVS FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.75&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=65V:3-({2-[1-(3-FLUORO-4-HYDROXYPHENYL)-1H-1,2,3-TRIAZOL-4-YL]QUINOLIN-5-YL}OXY)BENZOIC+ACID'>65V</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5hvs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hvs OCA], [https://pdbe.org/5hvs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5hvs RCSB], [https://www.ebi.ac.uk/pdbsum/5hvs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5hvs ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/MIF_HUMAN MIF_HUMAN] Genetic variations in MIF are associated with susceptibility to rheumatoid arthritis systemic juvenile (RASJ) [MIM:[https://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 ==
[https://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 ==
Human macrophage migration inhibitory factor (MIF) is both a keto-enol tautomerase and a cytokine associated with numerous inflammatory diseases and cancer. Consistent with observed correlations between inhibition of the enzymatic and biological activities, discovery of MIF inhibitors has focused on monitoring the tautomerase activity using l-dopachrome methyl ester or 4-hydroxyphenyl pyruvic acid as substrates. The accuracy of these assays is compromised by several issues including substrate instability, spectral interference, and short linear periods for product formation. In this work, we report the syntheses of fluorescently labeled MIF inhibitors and their use in the first fluorescence polarization-based assay to measure the direct binding of inhibitors to the active site. The assay allows the accurate and efficient identification of competitive, noncompetitive, and covalent inhibitors of MIF in a manner that can be scaled for high-throughput screening. The results for 22 compounds show that the most potent MIF inhibitors bind with Kd values of ca. 50 nM; two are from our laboratory, and the other is a compound from the patent literature. X-ray crystal structures for two of the most potent compounds bound to MIF are also reported here. Striking combinations of protein-ligand hydrogen bonding, aryl-aryl, and cation-pi interactions are responsible for the high affinities. A new chemical series was then designed using this knowledge to yield two more strong MIF inhibitors/binders.

A Fluorescence Polarization Assay for Binding to Macrophage Migration Inhibitory Factor and Crystal Structures for Complexes of Two Potent Inhibitors.,Cisneros JA, Robertson MJ, Valhondo M, Jorgensen WL J Am Chem Soc. 2016 Jun 28. PMID:27299179<ref>PMID:27299179</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5hvs" style="background-color:#fffaf0;"></div>

==See Also==
*[[Macrophage inhibitory factor 3D structures|Macrophage inhibitory factor 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Jorgensen WL]]
[[Category: Robertson MJ]]