3KER

D-Dopachrome tautomerase (D-DT)/ macrophage migration inhibitory factor 2 (MIF2) complexed with inhibitor 4-IPP

3KER の概要

• エントリーDOI: 10.2210/pdb3ker/pdb
• 関連するPDBエントリー: 1DPT 1MIF 3B64 3B9S 3KAN
• 分子名称: D-dopachrome decarboxylase, 4-phenylpyrimidine, CHLORIDE ION, ... (5 entities in total)
• 機能のキーワード: tautomerase, inflammation, cytokine, cytokine-inhibitor complex, cytokine/inhibitor
• 由来する生物種: Mus musculus (mouse)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 52982.04

構造登録者

Zierow, S.,Lolis, E. (登録日: 2009-10-26, 公開日: 2010-10-13, 最終更新日: 2024-11-27)

主引用文献

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

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: 25016026
DOI: 10.1096/fj.14-256636

実験手法

X-RAY DIFFRACTION (2.78 Å)