4C1M

Myeloperoxidase in complex with the revesible inhibitor HX1

4C1M の概要

• エントリーDOI: 10.2210/pdb4c1m/pdb
• 分子名称: MYELOPEROXIDASE LIGHT CHAIN, ACETATE ION, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (12 entities in total)
• 機能のキーワード: oxidoreductase, hydroxamate
• 由来する生物種: HOMO SAPIENS (HUMAN); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 137153.06

構造登録者

Forbes, L.V.,Sjogren, T.,Auchere, F.,Jenkins, D.W.,Thong, B.,Laughton, D.,Hemsley, P.,Pairaudeau, G.,Eriksson, H.,Unitt, J.F.,Kettle, A.J. (登録日: 2013-08-13, 公開日: 2013-11-13, 最終更新日: 2023-12-20)

主引用文献

Forbes, L.V.,Sjogren, T.,Auchere, F.,Jenkins, D.W.,Thong, B.,Laughton, D.,Hemsley, P.,Pairaudeau, G.,Turner, R.,Eriksson, H.,Unitt, J.F.,Kettle, A.J.
Potent Reversible Inhibition of Myeloperoxidase by Aromatic Hydroxamates
J.Biol.Chem., 288:36636-, 2013

PubMed Abstract: The neutrophil enzyme myeloperoxidase (MPO) promotes oxidative stress in numerous inflammatory pathologies by producing hypohalous acids. Its inadvertent activity is a prime target for pharmacological control. Previously, salicylhydroxamic acid was reported to be a weak reversible inhibitor of MPO. We aimed to identify related hydroxamates that are good inhibitors of the enzyme. We report on three hydroxamates as the first potent reversible inhibitors of MPO. The chlorination activity of purified MPO was inhibited by 50% by a 5 nm concentration of a trifluoromethyl-substituted aromatic hydroxamate, HX1. The hydroxamates were specific for MPO in neutrophils and more potent toward MPO compared with a broad range of redox enzymes and alternative targets. Surface plasmon resonance measurements showed that the strength of binding of hydroxamates to MPO correlated with the degree of enzyme inhibition. The crystal structure of MPO-HX1 revealed that the inhibitor was bound within the active site cavity above the heme and blocked the substrate channel. HX1 was a mixed-type inhibitor of the halogenation activity of MPO with respect to both hydrogen peroxide and halide. Spectral analyses demonstrated that hydroxamates can act variably as substrates for MPO and convert the enzyme to a nitrosyl ferrous intermediate. This property was unrelated to their ability to inhibit MPO. We propose that aromatic hydroxamates bind tightly to the active site of MPO and prevent it from producing hypohalous acids. This mode of reversible inhibition has potential for blocking the activity of MPO and limiting oxidative stress during inflammation.

PubMed: 24194519
DOI: 10.1074/JBC.M113.507756

実験手法

X-RAY DIFFRACTION (2 Å)