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4z15

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Revision as of 07:36, 19 June 2019

MIF in complex with 3-(2-furylmethyl)-2-thioxo-1,3-thiazolan-4-one

Structural highlights

4z15 is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
NonStd Res:
Related:	4z1u, 4z1t
Gene:	MIF, GLIF, MMIF (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[MIF_HUMAN] Genetic variations in MIF are associated with susceptibility to rheumatoid arthritis systemic juvenile (RASJ) [MIM: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

[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.^[1] ^[2]

Publication Abstract from PubMed

Macrophage migration inhibitory factor (MIF) is a master regulator of proinflammatory cytokines and plays pathological roles when not properly regulated in rheumatoid arthritis, lupus, atherosclerosis, asthma and cancer. Unlike canonical cytokines, MIF has vestigial keto-enol tautomerase activity. Most of the current MIF inhibitors were screened for the inhibition of this enzymatic activity. However, only some of the enzymatic inhibitors inhibit receptor-mediated biological functions of MIF, such as cell recruitment, through an unknown molecular mechanism. The goal of this study was to understand the molecular basis underlying the pharmacological inhibition of biological functions of MIF. Here, we demonstrate how the structural changes caused upon inhibitor binding translate into the alteration of MIF-induced downstream signalling. Macrophage migration inhibitory factor activates phosphoinositide 3-kinases (PI3Ks) that play a pivotal role in immune cell recruitment in health and disease. There are several different PI3K isoforms, but little is known about how they respond to MIF. We demonstrate that MIF up-regulates the expression of Class IB PI3Ks in leucocytes. We also demonstrate that MIF tautomerase active site inhibitors down-regulate the expression of Class IB PI3Ks as well as leucocyte recruitment in vitro and in vivo. Finally, based on our MIF:inhibitor complex crystal structures, we hypothesize that the reduction in Class IB PI3K expression occurs because of the displacement of Pro1 towards the second loop of MIF upon inhibitor binding, which results in increased flexibility of the loop 2 and sub-optimal MIF binding to its receptors. These results will provide molecular insights for fine-tuning the biological functions of MIF.

Structural basis for decreased induction of class IB PI3-kinases expression by MIF inhibitors.,Singh AK, Pantouris G, Borosch S, Rojanasthien S, Cho TY J Cell Mol Med. 2016 Sep 13. doi: 10.1111/jcmm.12949. PMID:27619729^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Oddo M, Calandra T, Bucala R, Meylan PR. Macrophage migration inhibitory factor reduces the growth of virulent Mycobacterium tuberculosis in human macrophages. Infect Immun. 2005 Jun;73(6):3783-6. PMID:15908412 doi:10.1128/IAI.73.6.3783-3786.2005
↑ Emonts M, Sweep FC, Grebenchtchikov N, Geurts-Moespot A, Knaup M, Chanson AL, Erard V, Renner P, Hermans PW, Hazelzet JA, Calandra T. Association between high levels of blood macrophage migration inhibitory factor, inappropriate adrenal response, and early death in patients with severe sepsis. Clin Infect Dis. 2007 May 15;44(10):1321-8. Epub 2007 Apr 5. PMID:17443469 doi:10.1086/514344
↑ Singh AK, Pantouris G, Borosch S, Rojanasthien S, Cho TY. Structural basis for decreased induction of class IB PI3-kinases expression by MIF inhibitors. J Cell Mol Med. 2016 Sep 13. doi: 10.1111/jcmm.12949. PMID:27619729 doi:http://dx.doi.org/10.1111/jcmm.12949

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4z15"

@@ Line 1: / Line 1: @@
 ==MIF in complex with 3-(2-furylmethyl)-2-thioxo-1,3-thiazolan-4-one==
-<StructureSection load='4z15' size='340' side='right' caption='[[4z15]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
+<StructureSection load='4z15' size='340' side='right'caption='[[4z15]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4z15]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Z15 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4Z15 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4z15]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Z15 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4Z15 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
 <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=4N8:1-[(FURAN-2-YLMETHYL)CARBAMOTHIOYL]-L-PROLINE'>4N8</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4z1u|4z1u]], [[4z1t|4z1t]]</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MIF, GLIF, MMIF ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4z15 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4z15 OCA], [http://pdbe.org/4z15 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4z15 RCSB], [http://www.ebi.ac.uk/pdbsum/4z15 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4z15 ProSAT]</span></td></tr>
 </table>
@@ Line 22: / Line 23: @@
 </div>
 <div class="pdbe-citations 4z15" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Macrophage inhibitory factor|Macrophage inhibitory factor]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Cho, T Y]]
 [[Category: Covalent inhibitor]]
 [[Category: Isomerase-isomerase inhibitor complex]]
 [[Category: Protein surface modification]]

4z15

From Proteopedia

Revision as of 07:36, 19 June 2019

MIF in complex with 3-(2-furylmethyl)-2-thioxo-1,3-thiazolan-4-one

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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