1ca7

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(New page: 200px<br /> <applet load="1ca7" size="450" color="white" frame="true" align="right" spinBox="true" caption="1ca7, resolution 2.5&Aring;" /> '''MACROPHAGE MIGRATION...)
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[[Image:1ca7.gif|left|200px]]<br />
 
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<applet load="1ca7" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1ca7, resolution 2.5&Aring;" />
 
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'''MACROPHAGE MIGRATION INHIBITORY FACTOR (MIF) WITH HYDROXPHENYLPYRUVATE'''<br />
 
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==Overview==
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==MACROPHAGE MIGRATION INHIBITORY FACTOR (MIF) WITH HYDROXPHENYLPYRUVATE==
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Macrophage migration inhibitory factor (MIF) is an important, immunoregulatory molecule with a unique ability to suppress the, anti-inflammatory effects of glucocorticoids. Although considered a, cytokine, MIF possesses a three-dimensional structure and active site, similar to those of 4-oxalocrotonate tautomerase and, 5-carboxymethyl-2-hydroxymuconate isomerase. Moreover, a number of, catalytic activities have been defined for MIF. To gain insight into the, role of catalysis in the biological function of MIF, we have begun to, characterize the catalytic activities in more detail. Here we report the, crystal structure of MIF complexed with p-hydroxyphenylpyruvate, a, substrate for the phenylpyruvate tautomerase activity of MIF. The three, binding sites for p-hydroxyphenylpyruvate in the MIF trimer lie at the, interface between two subunits. The substrate interacts with Pro-1, Lys-32, and Ile-64 from one subunit and Tyr-95 and Asn-97 from an adjacent, subunit. Pro-1 is positioned to function as a catalytic base. There is no, functional group that polarizes the alpha-carbonyl of the substrate to, weaken the adjacent C-H bond. Mutation of Pro-1 to glycine substantially, reduces the catalytic activity. The insertion of an alanine between Pro-1, and Met-2 essentially abolishes activity. Structural studies of these, mutants define a source of the reduced activity and provide insight into, the mechanism of the catalytic reaction.
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<StructureSection load='1ca7' size='340' side='right'caption='[[1ca7]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1ca7]] 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=1CA7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1CA7 FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EN1:(2E)-2-HYDROXY-3-(4-HYDROXYPHENYL)PROP-2-ENOIC+ACID'>EN1</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1ca7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ca7 OCA], [https://pdbe.org/1ca7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1ca7 RCSB], [https://www.ebi.ac.uk/pdbsum/1ca7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1ca7 ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[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.
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== Function ==
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[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>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ca/1ca7_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1ca7 ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Macrophage migration inhibitory factor (MIF) is an important immunoregulatory molecule with a unique ability to suppress the anti-inflammatory effects of glucocorticoids. Although considered a cytokine, MIF possesses a three-dimensional structure and active site similar to those of 4-oxalocrotonate tautomerase and 5-carboxymethyl-2-hydroxymuconate isomerase. Moreover, a number of catalytic activities have been defined for MIF. To gain insight into the role of catalysis in the biological function of MIF, we have begun to characterize the catalytic activities in more detail. Here we report the crystal structure of MIF complexed with p-hydroxyphenylpyruvate, a substrate for the phenylpyruvate tautomerase activity of MIF. The three binding sites for p-hydroxyphenylpyruvate in the MIF trimer lie at the interface between two subunits. The substrate interacts with Pro-1, Lys-32, and Ile-64 from one subunit and Tyr-95 and Asn-97 from an adjacent subunit. Pro-1 is positioned to function as a catalytic base. There is no functional group that polarizes the alpha-carbonyl of the substrate to weaken the adjacent C-H bond. Mutation of Pro-1 to glycine substantially reduces the catalytic activity. The insertion of an alanine between Pro-1 and Met-2 essentially abolishes activity. Structural studies of these mutants define a source of the reduced activity and provide insight into the mechanism of the catalytic reaction.
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==Disease==
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Pro-1 of macrophage migration inhibitory factor functions as a catalytic base in the phenylpyruvate tautomerase activity.,Lubetsky JB, Swope M, Dealwis C, Blake P, Lolis E Biochemistry. 1999 Jun 1;38(22):7346-54. PMID:10353846<ref>PMID:10353846</ref>
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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]]
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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1CA7 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 ENO as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1CA7 OCA].
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</div>
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<div class="pdbe-citations 1ca7" style="background-color:#fffaf0;"></div>
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==Reference==
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==See Also==
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Pro-1 of macrophage migration inhibitory factor functions as a catalytic base in the phenylpyruvate tautomerase activity., Lubetsky JB, Swope M, Dealwis C, Blake P, Lolis E, Biochemistry. 1999 Jun 1;38(22):7346-54. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=10353846 10353846]
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*[[Macrophage inhibitory factor 3D structures|Macrophage inhibitory factor 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Single protein]]
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[[Category: Large Structures]]
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[[Category: Lolis, E.]]
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[[Category: Lolis E]]
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[[Category: Lubetsky, J.B.]]
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[[Category: Lubetsky JB]]
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[[Category: ENO]]
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[[Category: cytokine]]
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[[Category: enzyme]]
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[[Category: protein hormone]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 16:19:01 2007''
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Current revision

MACROPHAGE MIGRATION INHIBITORY FACTOR (MIF) WITH HYDROXPHENYLPYRUVATE

PDB ID 1ca7

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