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4wr8

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Macrophage Migration Inhibitory Factor in complex with a biaryltriazole inhibitor (3b-180)

Structural highlights

4wr8 is a 18 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.6Å
Ligands:	, ,
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

Optimization is reported for biaryltriazoles as inhibitors of the tautomerase activity of human macrophage migration inhibitory factor (MIF), a proinflammatory cytokine associated with numerous inflammatory diseases and cancer. A combined approach was taken featuring organic synthesis, enzymatic assaying, crystallography, and modeling including free-energy perturbation (FEP) calculations. X-ray crystal structures for 3a and 3b bound to MIF are reported and provided a basis for the modeling efforts. The accommodation of the inhibitors in the binding site is striking with multiple hydrogen bonds and aryl-aryl interactions. Additional modeling encouraged pursuit of 5-phenoxyquinolinyl analogues, which led to the very potent compound 3s. Activity was further enhanced by addition of a fluorine atom adjacent to the phenolic hydroxyl group as in 3w, 3z, 3aa, and 3bb to strengthen a key hydrogen bond. It is also shown that physical properties of the compounds can be modulated by variation of solvent-exposed substituents. Several of the compounds are likely the most potent known MIF tautomerase inhibitors; the most active ones are more than 1000-fold more active than the well-studied (R)-ISO-1 and more than 200-fold more active than the chromen-4-one Orita-13.

Design, synthesis, and protein crystallography of biaryltriazoles as potent tautomerase inhibitors of macrophage migration inhibitory factor.,Dziedzic P, Cisneros JA, Robertson MJ, Hare AA, Danford NE, Baxter RH, Jorgensen WL J Am Chem Soc. 2015 Mar 4;137(8):2996-3003. doi: 10.1021/ja512112j. Epub 2015 Feb, 20. PMID:25697265^[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
↑ Dziedzic P, Cisneros JA, Robertson MJ, Hare AA, Danford NE, Baxter RH, Jorgensen WL. Design, synthesis, and protein crystallography of biaryltriazoles as potent tautomerase inhibitors of macrophage migration inhibitory factor. J Am Chem Soc. 2015 Mar 4;137(8):2996-3003. doi: 10.1021/ja512112j. Epub 2015 Feb, 20. PMID:25697265 doi:http://dx.doi.org/10.1021/ja512112j

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/4wr8"

Categories: Homo sapiens | Large Structures | Baxter RHG | Jorgensen WL | Robertson MJ

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4wr8]] is a 18 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=4WR8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4WR8 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3TX:4-[4-(QUINOLIN-2-YL)-1H-1,2,3-TRIAZOL-1-YL]PHENOL'>3TX</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.6&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3TX:4-[4-(QUINOLIN-2-YL)-1H-1,2,3-TRIAZOL-1-YL]PHENOL'>3TX</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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=4wr8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wr8 OCA], [https://pdbe.org/4wr8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4wr8 RCSB], [https://www.ebi.ac.uk/pdbsum/4wr8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4wr8 ProSAT]</span></td></tr>
 </table>

4wr8

From Proteopedia

Current revision

Macrophage Migration Inhibitory Factor in complex with a biaryltriazole inhibitor (3b-180)

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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