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NMR structure and localization of the host defense antimicrobial peptide thanatin in zwitterionic dodecylphosphocholine micelle: Implications in antimicrobial activity.
Biochimica et Biophysica Acta (BBA) - Biomembranes ( IF 3.4 ) Pub Date : 2020-08-08 , DOI: 10.1016/j.bbamem.2020.183432
Sheetal Sinha 1 , Wun Jern Ng 2 , Surajit Bhattacharjya 3
Affiliation  

Antimicrobial peptides (AMPs) are potentially vital as the next generation of antibiotics against multidrug resistant bacterial pathogens. Thanatin, an insect derived pathogen inducible 21-residue long antimicrobial peptide, demonstrates antimicrobial activity toward broad range of pathogens. Thanatin is an excellent candidate for antibiotics development due to potent in vivo activity in animal model and low toxicity to human cells. Recent studies indicated mode of action of thanatin could be intriguing and may comprise bacterial membrane permeabilization and interactions with periplasmic proteins. In order to better understand selectivity and membrane disruption, here, we determined 3-D structure of the thanatin in zwitterionic DPC-d38 micelle by NMR spectroscopy. The depth of insertion of thanatin into micelle structure was investigated by spin labelled doxyl lipids, 5-DSA and 16-DSA. DPC-bound structure of thanatin is defined by a β-hairpin structure and an extended and turn conformations, for residues G1-I8, at the N-terminus. The β-hairpin structure is delineated by two antiparallel β-strands, residues I9-C11 and residues K17-R20, which is connected by loop consisted of residues N12-G16. There are cross β-strands sidechain-sidechain packing interactions among hydrophobic and aromatic residues. Spin labelled lipid studies revealed a set of spatially proximal residues V6, I8, Q19, R20 and M21 may be deeply inserted into the hydrophobic core of the DPC micelle. While, residues including those at the turn/loop are merely surface localized. The atomic resolution structure and orientation of thanatin in zwitterionic DPC micelle may be utilized for understating mode of action in lipid membrane and further development of non-toxic analogs.



中文翻译:

两性离子十二烷基磷酸胆碱胶束中的宿主防御性抗菌肽thanatin的NMR结构和定位:抗菌活性的含义。

抗菌肽(AMPs)作为下一代抗多药耐药细菌病原体的抗生素具有潜在的重要性。Thanatin是一种昆虫衍生的病原体可诱导的21个残基长的抗菌肽,对多种病原体均具有抗菌活性。由于动物模型中的体内活性很强并且对人细胞的毒性低,因此,Thanatin是开发抗生素的绝佳候选者。最近的研究表明,thanatin的作用方式可能很有趣,可能包括细菌膜通透性以及与周质蛋白的相互作用。为了更好地理解选择性和膜破坏,在这里,我们确定了两性离子DPC-d 38中的坦那汀的3-D结构。NMR光谱测定胶束。通过旋转标记的二甲苯基脂质,5-DSA和16-DSA研究了坦那坦胶束结构的插入深度。thanatin的DPC结合结构由β-发夹结构以及N端残基G1-I8的延伸和转向构象定义。β-发夹结构由两个反平行的β链(残基I9-C11和残基K17-R20)描绘,它们通过由残基N12-G16组成的环相连。疏水残基和芳香残基之间存在交叉的β链侧链-侧链堆积相互作用。旋转标记脂质研究表明,一组空间近端残基V6,I8,Q19,R20和M21可能会深深插入DPC胶束的疏水核中。同时,残渣(包括在转弯/回路处的残渣)仅在表面定位。

更新日期:2020-08-11
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