Structure of the LpxC deacetylase with a bound substrate-analog inhibitor
Structure of the LpxC deacetylase with a bound substrate-analog inhibitor
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DOI：
10.1038/nsb948
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发表时间：
2003-08-01
期刊：
影响因子：
--
通讯作者：
Zhou, P
中科院分区：
文献类型：
--
作者：
Coggins, BE;Li, XC;Zhou, P
锌依赖性 UDP-3-O-酰基-N-乙酰氨基葡萄糖脱乙酰酶 (LpxC) 催化脂质 A 生物合成的第一个关键步骤，脂质 A 是构成革兰氏阴性细菌最外单层的脂多糖 (LPS) 的疏水锚。由于 LpxC 对于革兰氏阴性生物体的生存至关重要，并且与已知的哺乳动物脱乙酰酶或酰胺酶没有序列同源性，因此它是设计新抗生素的绝佳靶标。来自 Aquifex aeolicus 的 LpxC 与底物类似物抑制剂 TU-514 复合的溶液结构揭示了新的 α/β 折叠、独特的锌结合基序和捕获抑制剂酰基链的疏水通道。在生化和结构研究的基础上，我们提出了 LpxC 的催化机制，提出了底物结合模型，并提供了证据表明靠近活性位点的结构基序的移动性和动力学在底物的捕获中起着关键作用。
The zinc-dependent UDP-3-O-acyl-N-acetylglucosamine deacetylase ( LpxC) catalyzes the first committed step in the biosynthesis of lipid A, the hydrophobic anchor of lipopolysaccharide (LPS) that constitutes the outermost monolayer of Gram-negative bacteria. As LpxC is crucial for the survival of Gram-negative organisms and has no sequence homology to known mammalian deacetylases or amidases, it is an excellent target for the design of new antibiotics. The solution structure of LpxC from Aquifex aeolicus in complex with a substrate-analog inhibitor, TU-514, reveals a novel alpha/beta fold, a unique zinc-binding motif and a hydrophobic passage that captures the acyl chain of the inhibitor. On the basis of biochemical and structural studies, we propose a catalytic mechanism for LpxC, suggest a model for substrate binding and provide evidence that mobility and dynamics in structural motifs close to the active site have key roles in the capture of the substrate.