3KAN
D-dopachrome tautomerase (D-DT)/macrophage migration inhibitory factor 2 (MIF2) complexed with inhibitor 4-IPP
Summary for 3KAN
| Entry DOI | 10.2210/pdb3kan/pdb |
| Related | 1DPT 3B64 3B9S 3KER |
| Descriptor | D-dopachrome tautomerase, 4-phenylpyrimidine, CHLORIDE ION, ... (4 entities in total) |
| Functional Keywords | immune response, cytokine, tautomerase, cytokine-inhibitor complex, cytokine/inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 3 |
| Total formula weight | 38320.04 |
| Authors | Zierow, S.,Lolis, E. (deposition date: 2009-10-19, release date: 2011-04-20, Last modification date: 2024-11-06) |
| Primary citation | 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. Faseb J., 28:4961-4971, 2014 Cited by PubMed Abstract: 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 μg. 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 ∼ 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 Å 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. PubMed: 25016026DOI: 10.1096/fj.14-256636 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.13 Å) |
Structure validation
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