Jing Weiguo, Svendsen John S, Vogel Hans J
Structural Biology Research Group, Department of Biological Sciences, University of Calgary, Calgary, AB T2N 1N4, Canada.
Biochem Cell Biol. 2006 Jun;84(3):312-26. doi: 10.1139/o06-052.
LFB (FKCRRWQWRMKKLGA-HN2) is a 15-residue linear antimicrobial peptide derived from bovine lactoferricin, which has antimicrobial activity similar to that of the intact 25-residue disulfide-cyclized peptide. Previous alanine-scan studies, in which all of the residues in LFB were individually replaced with Ala, showed that the 2 tryptophan (Trp) residues of LFB were crucial to its antimicrobial activity. When either Trp6 or Trp8 was replaced with Ala (LFBA6 and LFBA8, respectively), these 2 peptides were almost devoid of antimicrobial activity. We determined the structures of LFB, LFBA6, and LFBA8 bound to membrane-mimetic SDS micelles using NMR spectroscopy, and studied their interactions with different phospholipid-model membranes. The membrane interactions of LFB exhibited little correlation with its antimicrobial activity, suggesting that the mechanism of action of LFB involves intracellular targets. However, the much higher antimicrobial activity of LFB compared with LFBA6 and LFBA8 might result, in part, from the formation of energetically favorable cation-pi interactions observed only in LFB. Information about the importance of Arg and Trp cation-pi interactions will provide insight for the future design of potent antimicrobial peptidomimetics.
乳铁蛋白衍生肽（FKCRRWQWRMKKLGA-HN2）是一种由牛乳铁传递蛋白素衍生而来的含15个氨基酸残基的线性抗菌肽，其抗菌活性与完整的含25个氨基酸残基的二硫键环化肽相似。先前的丙氨酸扫描研究中，乳铁蛋白衍生肽中的所有残基都被逐个替换为丙氨酸，结果表明乳铁蛋白衍生肽的2个色氨酸（Trp）残基对其抗菌活性至关重要。当Trp6或Trp8被替换为丙氨酸时（分别为LFBA6和LFBA8），这两种肽几乎没有抗菌活性。我们使用核磁共振光谱法测定了与模拟膜的SDS胶束结合的乳铁蛋白衍生肽、LFBA6和LFBA8的结构，并研究了它们与不同磷脂模型膜的相互作用。乳铁蛋白衍生肽的膜相互作用与其抗菌活性几乎没有相关性，这表明乳铁蛋白衍生肽的作用机制涉及细胞内靶点。然而，与LFBA6和LFBA8相比，乳铁蛋白衍生肽更高的抗菌活性可能部分源于仅在乳铁蛋白衍生肽中观察到的能量有利的阳离子-π相互作用的形成。关于精氨酸和色氨酸阳离子-π相互作用重要性的信息将为未来设计有效的抗菌模拟肽提供见解。
