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==D-dopachrome tautomerase (D-DT)/macrophage migration inhibitory factor 2 (MIF2) complexed with inhibitor 4-IPP== | ==D-dopachrome tautomerase (D-DT)/macrophage migration inhibitory factor 2 (MIF2) complexed with inhibitor 4-IPP== | ||
<StructureSection load='3kan' size='340' side='right' caption='[[3kan]], [[Resolution|resolution]] 1.13Å' scene=''> | <StructureSection load='3kan' size='340' side='right'caption='[[3kan]], [[Resolution|resolution]] 1.13Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3kan]] 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=3KAN OCA]. For a <b>guided tour on the structure components</b> use [http:// | <table><tr><td colspan='2'>[[3kan]] 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=3KAN OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=3KAN FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=RW1:4-PHENYLPYRIMIDINE'>RW1</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=RW1:4-PHENYLPYRIMIDINE'>RW1</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3b9s|3b9s]], [[3b64|3b64]], [[1dpt|1dpt]], [[3ker|3ker]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3b9s|3b9s]], [[3b64|3b64]], [[1dpt|1dpt]], [[3ker|3ker]]</td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DDT, hCG_41098 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DDT, hCG_41098 ([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:// | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=3kan FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3kan OCA], [http://pdbe.org/3kan PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3kan RCSB], [http://www.ebi.ac.uk/pdbsum/3kan PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3kan ProSAT]</span></td></tr> | ||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
We report a new inflammatory activity for extracellular d-dopachrome tautomerase (D-DT), the recruitment of neutrophils to the lung on D-DT intratracheal installation of C57BL/6J mice with an EC50 of 5.6 mug. We also find that D-DT and macrophage migration inhibitory factor (MIF) have additive effects in neutrophil recruitment. Although the tautomerase site of D-DT and its homologue MIF are biophysically very different, 4-iodo-6-phenylpyrimidine (4-IPP) forms a covalent bond with Pro-1 of both proteins, resulting in a 6-phenylpyrimidine (6-PP) adduct. Recruitment of neutrophils to the lung for the 6-PP adducts of D-DT and MIF are reduced by approximately 50% relative to the apo proteins, demonstrating that an unmodified Pro-1 is important for this activity, but there is no cooperativity in inhibition of the proteins together. The differences in the binding mode of the 6-PP adduct for D-DT was determined by crystallographic studies at 1.13 A resolution and compared to the structure of the MIF-6-PP complex. There are major differences in the location of the 6-PP adduct to the D-DT and MIF active sites that provide insight into the lack of cooperativity by 4-IPP and into tuning the properties of the covalent inhibitors of D-DT and MIF that are necessary for the development of therapeutic small molecules against neutrophil damage from lung infections such as Pseudomonas aeruginosa in cystic fibrosis and immunocompromised patients.-Rajasekaran, D., Zierow, S., Syed, M., Bucala, R., Bhandari, V., Lolis, E. J. Targeting distinct tautomerase sites of D-DT and MIF with a single molecule for inhibition of neutrophil lung recruitment. | |||
Targeting distinct tautomerase sites of D-DT and MIF with a single molecule for inhibition of neutrophil lung recruitment.,Rajasekaran D, Zierow S, Syed M, Bucala R, Bhandari V, Lolis EJ FASEB J. 2014 Jul 11. pii: fj.14-256636. PMID:25016026<ref>PMID:25016026</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3kan" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | [[Category: Human]] | ||
[[Category: Large Structures]] | |||
[[Category: Lolis, E]] | [[Category: Lolis, E]] | ||
[[Category: Zierow, S]] | [[Category: Zierow, S]] | ||
Revision as of 11:20, 21 October 2020
D-dopachrome tautomerase (D-DT)/macrophage migration inhibitory factor 2 (MIF2) complexed with inhibitor 4-IPPD-dopachrome tautomerase (D-DT)/macrophage migration inhibitory factor 2 (MIF2) complexed with inhibitor 4-IPP
Structural highlights
Publication Abstract from PubMedWe report a new inflammatory activity for extracellular d-dopachrome tautomerase (D-DT), the recruitment of neutrophils to the lung on D-DT intratracheal installation of C57BL/6J mice with an EC50 of 5.6 mug. We also find that D-DT and macrophage migration inhibitory factor (MIF) have additive effects in neutrophil recruitment. Although the tautomerase site of D-DT and its homologue MIF are biophysically very different, 4-iodo-6-phenylpyrimidine (4-IPP) forms a covalent bond with Pro-1 of both proteins, resulting in a 6-phenylpyrimidine (6-PP) adduct. Recruitment of neutrophils to the lung for the 6-PP adducts of D-DT and MIF are reduced by approximately 50% relative to the apo proteins, demonstrating that an unmodified Pro-1 is important for this activity, but there is no cooperativity in inhibition of the proteins together. The differences in the binding mode of the 6-PP adduct for D-DT was determined by crystallographic studies at 1.13 A resolution and compared to the structure of the MIF-6-PP complex. There are major differences in the location of the 6-PP adduct to the D-DT and MIF active sites that provide insight into the lack of cooperativity by 4-IPP and into tuning the properties of the covalent inhibitors of D-DT and MIF that are necessary for the development of therapeutic small molecules against neutrophil damage from lung infections such as Pseudomonas aeruginosa in cystic fibrosis and immunocompromised patients.-Rajasekaran, D., Zierow, S., Syed, M., Bucala, R., Bhandari, V., Lolis, E. J. Targeting distinct tautomerase sites of D-DT and MIF with a single molecule for inhibition of neutrophil lung recruitment. Targeting distinct tautomerase sites of D-DT and MIF with a single molecule for inhibition of neutrophil lung recruitment.,Rajasekaran D, Zierow S, Syed M, Bucala R, Bhandari V, Lolis EJ FASEB J. 2014 Jul 11. pii: fj.14-256636. PMID:25016026[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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