5j7p

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Macrophage Migration Inhibitory Factor bound to Covalent Inhibitor RDR03785

Structural highlights

5j7p is a 3 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 1.85Å
Ligands:6H1, GOL, IPA, SO4
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

Inhibitors of human macrophage migration inhibitory factor (MIF) previously reported in the literature have been reexamined by synthesis, assaying for tautomerase activity, and protein crystallography. Substantial inconsistencies between prior and current assay results are noted. They appear to arise from difficulties with the tautomerase substrates, solubility issues, and especially covalent inhibition. Incubation time variation shows that 3, 4, 6, and 9 are covalent or slow-binding inhibitors. Two protein crystal structures are provided; one confirms that the twice-discovered 3 is a covalent inhibitor.

Irregularities in enzyme assays: The case of macrophage migration inhibitory factor.,Cisneros JA, Robertson MJ, Valhondo M, Jorgensen WL Bioorg Med Chem Lett. 2016 Jun 15;26(12):2764-7. doi: 10.1016/j.bmcl.2016.04.074., Epub 2016 Apr 26. PMID:27156768[3]

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

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Citations
1 reviews cite this structure
Small-molecule inhibitors of macrophage migration inhibitory factor (MIF) as an emerging class of therapeutics for immune disorders.
Kok et al. (2018)
0 more
11 other articles
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See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ Cisneros JA, Robertson MJ, Valhondo M, Jorgensen WL. Irregularities in enzyme assays: The case of macrophage migration inhibitory factor. Bioorg Med Chem Lett. 2016 Jun 15;26(12):2764-7. doi: 10.1016/j.bmcl.2016.04.074., Epub 2016 Apr 26. PMID:27156768 doi:http://dx.doi.org/10.1016/j.bmcl.2016.04.074

Contents


PDB ID 5j7p

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OCA

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