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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Structure of UDP-N-acetylglucosamine acyltransferase with a bound antibacterial pentadecapeptide
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Structure of UDP-N-acetylglucosamine acyltransferase with a bound antibacterial pentadecapeptide

机译：结合有抗菌五肽的UDP-N-乙酰氨基葡糖酰基转移酶的结构

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摘要

UDP-GIcNAc acyltransferase (LpxA) catalyzes the first step of lipid A biosynthesis, the transfer of the R-3-hydroxyacyl chain from R-3-hydroxyacyl acyl carrier protein (ACIP) to the glucosamine 3-OH group of UDP-GIcNAc. LpxA is essential for the growth of Escherichia coli and related Gram-negative bacteria. The crystal structure of the E. coli LpxA homotrimer, determined previously at 2.6 angstrom in the absence of substrates or inhibitors, revealed that LpxA contains an unusual, left-handed parallel beta-helix fold. We now present the crystal structure at 1.8 angstrom resolution of E. coli LpxA in a complex with a pentadecapeptide, peptide 920. Three peptides, each of which adopts a beta-hairpin conformation, are bound per LpxA trimer. The peptides are located at the interfaces of adjacent subunits in the vicinity of the three active sites. Each peptide interacts with residues from both adjacent subunits. Peptide 920 is a potent inhibitor of E. coli LpxA (K-i = 50 nM). It is competitive with respect to acyl-ACP but not UDP-GIcNAc. The compact P-turn structure of peptide 920 bound to LpxA may open previously uncharacterized approaches to the rational design of LpxA inhibitors with antibiotic activity.
机译：UDP-GIcNAc酰基转移酶（LpxA）催化脂质A生物合成的第一步，即R-3-羟基酰基链从R-3-羟基酰基载体蛋白（ACIP）转移到UDP-GIcNAc的氨基葡萄糖3-OH基团。 LpxA对于大肠杆菌和相关革兰氏阴性细菌的生长至关重要。在没有底物或抑制剂的情况下，以前在2.6埃下测定的大肠杆菌LpxA同型三聚体的晶体结构显示LpxA包含不寻常的左手平行β-螺旋折叠。现在，我们在大肠杆菌LpxA与五肽，肽920的复合物中呈现1.8埃分辨率的晶体结构。每个LpxA三聚体都结合了三个肽，每个肽均采用β-发夹结构。所述肽位于三个活性位点附近的相邻亚基的界面处。每个肽与来自两个相邻亚基的残基相互作用。肽920是大肠杆菌LpxA的有效抑制剂（K-1 = 50 nM）。就酰基-ACP而言，它具有竞争力，但与UDP-GIcNAc相比则没有竞争力。与LpxA结合的肽920的紧凑的P字转折结构可能为合理设计具有抗生素活性的LpxA抑制剂打开以前未表征的方法。

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