Hsu Shang-Te D, Breukink Eefjan, Bierbaum Gabriele, Sahl Hans-Georg, de Kruijff Ben, Kaptein Rob, van Nuland Nico A J, Bonvin Alexandre M J J
NMR Department, Bijvoet Center for Biomolecular Research, Utrecht University, 3584CH, Utrecht, The Netherlands.
J Biol Chem. 2003 Apr 11;278(15):13110-7. doi: 10.1074/jbc.M211144200. Epub 2003 Jan 31.
Mersacidin belongs to the type B lantibiotics (lanthionine-containing antibiotics) that contain post-translationally modified amino acids and cyclic ring structures. It targets the cell wall precursor lipid II and thereby inhibits cell wall synthesis. In light of the emerging antibiotics resistance problem, the understanding of the antibacterial activity on a structural basis provides a key to circumvent this issue. Here we present solution NMR studies of mersacidin-lipid II interaction in dodecylphosphocholine (DPC) micelles. Distinct solution structures of mersacidin were determined in three different states: in water/methanol solution and in DPC micelles with and without lipid II. The structures in various sample conditions reveal remarkable conformational changes in which the junction between Ala-12 and Abu-13 (where Abu is aminobutyric acid) effectively serves as the hinge for the opening and closure of the ring structures. The DPC micelle-bound form resembles the previously determined NMR and x-ray crystal structures of mersacidin in pure methanol but substantially deviates from the other two states in our current report. The structural changes delineate the large chemical shift perturbations observed during the course of a two-step (15)N-(1)H heteronuclear single quantum coherence titration. They also modulate the surface charge distribution of mersacidin suggesting that electrostatics play a central role in the mersacidin-lipid II interaction. The observed conformational adaptability of mersacidin might be a general feature of lipid II-interacting antibiotics/peptides.
默诺菌素属于B型羊毛硫抗生素（含羊毛硫氨酸的抗生素），这类抗生素含有翻译后修饰的氨基酸和环状结构。它作用于细胞壁前体脂II，从而抑制细胞壁合成。鉴于新出现的抗生素耐药性问题，从结构角度理解其抗菌活性为解决这一问题提供了关键。在此，我们展示了在十二烷基磷酸胆碱（DPC）胶束中默诺菌素与脂II相互作用的溶液核磁共振研究。在三种不同状态下确定了默诺菌素独特的溶液结构：在水/甲醇溶液中以及在有和没有脂II的DPC胶束中。各种样品条件下的结构揭示了显著的构象变化，其中丙氨酸-12和氨基丁酸（Abu）-13之间的连接有效地充当了环结构打开和关闭的铰链。与DPC胶束结合的形式类似于之前在纯甲醇中确定的默诺菌素的核磁共振和X射线晶体结构，但与我们当前报告中的其他两种状态有很大偏差。这些结构变化描绘了在两步（15）N-（1）H异核单量子相干滴定过程中观察到的大化学位移扰动。它们还调节了默诺菌素的表面电荷分布，表明静电作用在默诺菌素与脂II的相互作用中起核心作用。观察到的默诺菌素的构象适应性可能是与脂II相互作用的抗生素/肽的一个普遍特征。
