Structural origin of endotoxin neutralization and antimicrobial activity of a lactoferrin-based peptide
Structural origin of endotoxin neutralization and antimicrobial activity of a lactoferrin-based peptide
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DOI：
10.1074/jbc.m500266200
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发表时间：
2005-04-29
影响因子：
4.8
通讯作者：
Jerala, R
中科院分区：
文献类型：
--
作者：
Japelj, B;Pristovsek, P;Jerala, R
用抗微生物剂治疗革兰氏阴性细菌感染可引起内毒素脂多糖（LPS）的释放，内毒素脂多糖是脓毒症的有效引发剂，脓毒症是全世界重症监护病房死亡的主要原因。与LPS结合的肽的结构信息可以导致更有效的内毒素中和剂的开发。基于人乳铁蛋白的短线性抗微生物和内毒素中和肽LF11与LPS结合，诱导具有疏水核心的“T形”排列和与LPS的两个磷酸基团之间的距离匹配的两簇碱性残基的肽折叠。结合LPS的LF11的侧链排列扩展了先前提出的LPS结合模式，强调了在限定的几何排列中静电和疏水相互作用的重要性。在阴离子胶束中，LF11形成具有比LPS更小的疏水核心的两亲性构象，而在两性离子胶束中，结构甚至更不确定。色氨酸荧光猝灭的保护顺序为SDS> LPS> DPC和氢交换保护，表明N端插入程度的降低和肽可塑性在细菌和真核细胞膜之间的分化中的潜在作用。
Treatment of Gram-negative bacterial infections with antimicrobial agents can cause release of the endotoxin lipopolysaccharide (LPS), the potent initiator of sepsis, which is the major cause of mortality in intensive care units worldwide. Structural information on peptides bound to LPS can lead to the development of more effective endotoxin neutralizers. Short linear antimicrobial and endotoxin-neutralizing peptide LF11, based on the human lactoferrin, binds to LPS, inducing a peptide fold with a "T-shaped" arrangement of a hydrophobic core and two clusters of basic residues that match the distance between the two phosphate groups of LPS. Side chain arrangement of LF11 bound to LPS extends the previously proposed LPS binding pattern, emphasizing the importance of both electrostatic and hydrophobic interactions in a defined geometric arrangement. In anionic micelles, the LF11 forms amphipathic conformation with a smaller hydrophobic core than in LPS, whereas in zwitterionic micelles, the structure is even less defined. Protection of tryptophan fluorescence quenching in the order SDS> LPS> DPC and hydrogen exchange protection indicates the decreasing extent of insertion of the N terminus and potential role of peptide plasticity in differentiation between bacterial and eukaryotic membranes.