View source for 3wns


==Allyl isothiocyanate inhibitor complexed with Macrophage Migration Inhibitory Factor==
<StructureSection load='3wns' size='340' side='right'caption='[[3wns]], [[Resolution|resolution]] 1.66&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3wns]] 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=3WNS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3WNS 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]] 1.658&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9AI:N-PROP-2-EN-1-YLTHIOFORMAMIDE'>9AI</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</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=3wns FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3wns OCA], [https://pdbe.org/3wns PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3wns RCSB], [https://www.ebi.ac.uk/pdbsum/3wns PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3wns 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 ==
Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that has roles in the innate immune response, and also contributes to inflammatory disease. While the biological properties of MIF are closely linked to protein-protein interactions, MIF also has tautomerase activity. Inhibition of this activity interferes with the interaction of MIF with protein partners e.g. the CD74 receptor, and tautomerase inhibitors show promise in disease models including multiple sclerosis and colitis. Isothiocyanates inhibit MIF tautomerase activity via covalent modification of the N-terminal proline. We systematically explored variants of benzyl and phenethyl isothiocyanates, to define determinants of inhibition. In particular, substitution with hydroxyl, chloro, fluoro and trifluoro moieties at the para and meta positions were evaluated. In assays on treated cells and recombinant protein, the IC50 varied from 250 nM to &gt;100 muM. X-ray crystal structures of selected complexes revealed that two binding modes are accessed by some compounds, perhaps owing to strain in short linkers between the isothiocyanate and aromatic ring. The variety of binding modes confirms the existence of two subsites for inhibitors and establishes a platform for the development of potent inhibitors of MIF that only need to target one of these subsites.

Multiple binding modes of isothiocyanates that inhibit macrophage migration inhibitory factor.,Spencer ES, Dale EJ, Gommans AL, Rutledge MT, Vo CT, Nakatani Y, Gamble AB, Smith RA, Wilbanks SM, Hampton MB, Tyndall JD Eur J Med Chem. 2015 Mar 26;93:501-10. doi: 10.1016/j.ejmech.2015.02.012. Epub, 2015 Feb 24. PMID:25743213<ref>PMID:25743213</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 3wns" 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: Dale EJ]]
[[Category: Gamble AB]]
[[Category: Gommans AL]]
[[Category: Hampton MB]]
[[Category: Rutledge MT]]
[[Category: Smith RAJ]]
[[Category: Spencer ES]]
[[Category: Tyndall JDA]]
[[Category: Wilbanks SM]]