Membrane Structural and Functional Biology (MS&FB) Group, School of Medicine and School of Biochemistry and Immunology, Trinity College Dublin, Dublin 2, Ireland.
Swiss Light Source, Paul Scherrer Institute, CH-5232 Villigen, Switzerland.
Nat Commun. 2017 Jul 4;8:15952. doi: 10.1038/ncomms15952.
Lipoproteins serve essential roles in the bacterial cell envelope. The posttranslational modification pathway leading to lipoprotein synthesis involves three enzymes. All are potential targets for the development of new antibiotics. Here we report the crystal structure of the last enzyme in the pathway, apolipoprotein N-acyltransferase, Lnt, responsible for adding a third acyl chain to the lipoprotein's invariant diacylated N-terminal cysteine. Structures of Lnt from Pseudomonas aeruginosa and Escherichia coli have been solved; they are remarkably similar. Both consist of a membrane domain on which sits a globular periplasmic domain. The active site resides above the membrane interface where the domains meet facing into the periplasm. The structures are consistent with the proposed ping-pong reaction mechanism and suggest plausible routes by which substrates and products enter and leave the active site. While Lnt may present challenges for antibiotic development, the structures described should facilitate design of therapeutics with reduced off-target effects.
脂蛋白在细菌细胞包膜中发挥着重要作用。导致脂蛋白合成的翻译后修饰途径涉及三种酶。所有这些酶都是开发新型抗生素的潜在靶点。在这里，我们报告了该途径中最后一种酶，载脂蛋白 N-酰基转移酶 Lnt 的晶体结构，该酶负责在脂蛋白不变的二酰化 N 端半胱氨酸上添加第三个酰基链。已解决铜绿假单胞菌和大肠杆菌中 Lnt 的结构；它们非常相似。两者都由一个位于其上的膜结构域和一个位于膜结构域上的球状周质结构域组成。活性位点位于膜界面上方，两个结构域在周质中相对。这些结构与所提出的乒乓反应机制一致，并提出了底物和产物进入和离开活性位点的可能途径。虽然 Lnt 可能对抗生素的开发提出挑战，但所描述的结构应该有助于设计具有降低的非靶标效应的治疗药物。
