Structure of the deacetylase LpxC bound to the antibiotic CHIR-090: Time-dependent inhibition and specificity in ligand binding
Structure of the deacetylase LpxC bound to the antibiotic CHIR-090: Time-dependent inhibition and specificity in ligand binding
复制标题
与抗生素 CHIR-090 结合的脱乙酰酶 LpxC 的结构：配体结合的时间依赖性抑制和特异性
DOI：
10.1073/pnas.0709412104
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发表时间：
2007-11-20
影响因子：
11.1
通讯作者：
Zhou, Pei
中科院分区：
文献类型：
--
作者：
Barb, Adam W.;Jiang, Ling;Zhou, Pei
UDP-3-O-（R-3-羟酰基）-N-乙酰葡糖胺脱乙酰基酶LpxC是革兰氏阴性菌中类脂A生物合成的必需酶，是一种很有前途的抗生素靶标。CHIR-090是迄今为止发现的最有效的LpxC抑制剂，显示出两步时间依赖性抑制作用，并与环丙沙星或妥布霉素一样有效地杀死各种革兰氏阴性病原体。在这项研究中，我们报告了LpxC-CHIR-090复合物的溶液结构。CHIR-090利用了LpxC的保守特征，这些特征对催化至关重要，包括疏水通道和必需的活性位点残基。CHIR-090邻近但不占据LpxC的UDP结合口袋，这表明基于片段的方法可能有助于进一步优化LpxC抑制剂。此外，我们鉴定了插入物II疏水通道中调节时间依赖性抑制和CHIR-090抗性的关键残基。CHIR-090与其他小分子抗生素（如靶向LpxC的L-161，240）具有相似的化学支架，尽管以前未被识别，并为理解这些抑制剂的结合模式提供了模板。与该模型一致，我们提供了L-161，240也占据疏水通道的证据。
The UDP-3-O-(R-3-hydroxyacyl)-N-acetylglucosamine deacetylase LpxC is an essential enzyme of lipid A biosynthesis in Gram-negative bacteria and a promising antibiotic target. CHIR-090, the most potent LpxC inhibitor discovered to date, displays two-step time-dependent inhibition and kills a wide range of Gram-negative pathogens as effectively as ciprofloxacin or tobramycin. In this study, we report the solution structure of the LpxC–CHIR-090 complex. CHIR-090 exploits conserved features of LpxC that are critical for catalysis, including the hydrophobic passage and essential active-site residues. CHIR-090 is adjacent to, but does not occupy, the UDP-binding pocket of LpxC, suggesting that a fragment-based approach may facilitate further optimization of LpxC inhibitors. Additionally, we identified key residues in the Insert II hydrophobic passage that modulate time-dependent inhibition and CHIR-090 resistance. CHIR-090 shares a similar, although previously unrecognized, chemical scaffold with other small-molecule antibiotics such as L-161,240 targeting LpxC, and provides a template for understanding the binding mode of these inhibitors. Consistent with this model, we provide evidence that L-161,240 also occupies the hydrophobic passage.