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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Selective reciprocity in antimicrobial activity versus cytotoxicity of hBD-2 and crotamine
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Selective reciprocity in antimicrobial activity versus cytotoxicity of hBD-2 and crotamine

机译:抗菌活性与hBD-2和巴豆胺的细胞毒性的选择性交互作用

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摘要

Recent discoveries suggest cysteine-stabilized toxins and antimicrobial peptides have structure-activity parallels derived by common ancestry. Here, human antimicrobial peptide hBD-2 and rattlesnake venom-toxin crotamine were compared in phylogeny, 3D structure, target cell specificity, and mechanisms of action. Results indicate a striking degree of structural and phylogenetic congruence. Importantly, these polypeptides also exhibited functional reciprocity: (i) they exerted highly similar antimicrobial pH optima and spectra; (ii) both altered membrane potential consistent with ion channel-perturbing activities; and (iii) both peptides induced phosphatidylserine accessibility in eukaryotic cells. However, the Na_v channel-inhibitor tetrodotoxin antagonized hBD-2 mechanisms, but not those of crotamine. As crotamine targets eukaryotic ion channels, computational docking was used to compare hBD-2 versus crotamine interactions with prototypic bacterial, fungal, or mammalian K_v channels. Models support direct interactions of each peptide with K_v channels. However, while crotamine localized to occlude K_v channels in eukaryotic but not prokaryotic cells, hBD-2 interacted with prokaryotic and eukaryotic K_v channels but did not occlude either. Together, these results support the hypothesis that antimicrobial and cytotoxic polypeptides have ancestral structure-function homology, but evolved to preferentially target respective microbial versus mammalian ion channels via residue-specific interactions. These insights may accelerate development of anti-infective or therapeutic peptides that selectively target microbial or abnormal host cells.
机译:最近的发现表明,半胱氨酸稳定的毒素和抗菌肽具有共同祖先的结构活性相似性。在这里,比较了人类抗菌肽hBD-2和响尾蛇毒毒素巴豆胺的系统发育,3D结构,靶细胞特异性和作用机理。结果表明了惊人的结构和系统发育一致性。重要的是,这些多肽还表现出功能上的可逆性:(i)它们发挥了极为相似的抗菌pH最佳值和光谱; (ii)改变的膜电位均与离子通道的扰动相一致; (iii)两种肽均可在真核细胞中诱导磷脂酰丝氨酸的可及性。但是,Na_v通道抑制剂河豚毒素拮抗hBD-2的机制,而不是巴豆胺的机制。由于巴豆胺靶向真核离子通道,因此使用计算对接来比较hBD-2与巴豆胺与原型细菌,真菌或哺乳动物K_v通道的相互作用。模型支持每种肽与K_v通道的直接相互作用。然而,尽管巴豆胺定位成在真核细胞中阻断了K_v通道,但没有在原核细胞中阻断,但hBD-2与原核和真核K_v通道相互作用,但两者均没有阻断。总之,这些结果支持以下假设:抗微生物和细胞毒性多肽具有祖先结构-功能同源性,但进化为优先通过残基特异性相互作用靶向各自的微生物对哺乳动物离子通道。这些见解可以加速选择性靶向微生物或异常宿主细胞的抗感染或治疗性肽的开发。

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  • 作者单位

    Division of Infectious Diseases, LAC-Harbor University of California, Los Angeles Medical Center, Torrance, CA 90509 St. John's Cardiovascular Research Center, Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles, Torrance, CA 90502;

    Division of Infectious Diseases, LAC-Harbor University of California, Los Angeles Medical Center, Torrance, CA 90509 St. John's Cardiovascular Research Center, Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles, Torrance, CA 90502;

    Department of Experimental Medicine, Section of Chemistry and Structural Biology, University of Parma, 43100 Parma, Italy;

    Department of Chemistry and Center for Macromolecular Modeling and Materials Design, California State Polytechnic University, Pomona, CA 91768;

    Department of Chemistry and Center for Macromolecular Modeling and Materials Design, California State Polytechnic University, Pomona, CA 91768;

    Department of Chemistry and Center for Macromolecular Modeling and Materials Design, California State Polytechnic University, Pomona, CA 91768;

    Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, CA 90024;

    Division of Infectious Diseases, LAC-Harbor University of California, Los Angeles Medical Center, Torrance, CA 90509 St. John's Cardiovascular Research Center, Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles, Torrance, CA 90502 Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, CA 90024;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    channel; defensin; host defense; toxin;

    机译:渠道;防御素;主机防御;毒素;

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