Nitroreductases catalyse the NAD(P)H-dependent nitro reduction in nitrofuran antibiotics, which activates them into cytotoxic molecules leading to cell death. The design of new effective nitrofuran antibiotics relies on knowledge of the kinetic mechanism and nitrofuran binding mode of microbial nitroreductases NfsA and NfsB. This has been hampered by multiple co-crystallisation studies revealing ligand binding in non-electron transfer competent states. In a recent study by Day et al. (2021) the authors investigated the likely reaction mechanism and mode of nitrofurantoin binding to NfsA using potentiometry, global kinetics analysis, crystallography and molecular dynamics simulations. Their findings suggest nitrofurantoin reduction proceeds via a direct hydride transfer from reduced FMN, while the crystallographic binding orientation is an inhibitory complex. Molecular dynamics simulations suggest ligand binding orientations is dependent on the oxidation state of the FMN. This study highlights the importance of utilising computational studies alongside traditional crystallographic approaches, when multiple stable ligand binding orientations can occur.

中文翻译：

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黄素氧化态对硝基还原酶中硝基呋喃抗生素结合方向的影响

硝基还原酶催化硝基呋喃抗生素中 NAD(P)H 依赖性硝基还原，这将它们激活成导致细胞死亡的细胞毒性分子。新型有效硝基呋喃抗生素的设计依赖于微生物硝基还原酶 NfsA 和 NfsB 的动力学机制和硝基呋喃结合模式的知识。这受到多项共结晶研究的阻碍，这些研究揭示了配体在非电子转移状态下的结合。在 Day 等人最近的一项研究中。(2021) 作者使用电位测定法、全局动力学分析、晶体学和分子动力学模拟研究了呋喃妥因与 NfsA 结合的可能反应机制和模式。他们的发现表明呋喃妥因还原是通过从还原的 FMN 中直接转移氢化物进行的，而晶体结合方向是一种抑制性复合物。分子动力学模拟表明配体结合方向取决于 FMN 的氧化态。当可能出现多个稳定的配体结合方向时，这项研究强调了将计算研究与传统晶体学方法结合使用的重要性。