The Antibacterial Cell Division Inhibitor PC190723 Is an FtsZ Polymer-stabilizing Agent That Induces Filament Assembly and Condensation
The Antibacterial Cell Division Inhibitor PC190723 Is an FtsZ Polymer-stabilizing Agent That Induces Filament Assembly and Condensation
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DOI：
10.1074/jbc.m109.094722
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发表时间：
2010-05-07
影响因子：
4.8
通讯作者：
Martin-Galiano, Antonio J.
中科院分区：
文献类型：
--
作者：
Andreu, Jose M.;Schaffner-Barbero, Claudia;Martin-Galiano, Antonio J.
细胞分裂蛋白FtsZ可以通过自转换组装形成具有协同行为的单链丝。随后FtsZ细丝的凝聚和弯曲对于细胞动力学环的形成和收缩非常重要。PC 190723是一种有效的杀菌细胞分裂抑制剂，其靶向病原体金黄色葡萄球菌和枯草芽孢杆菌中的FtsZ，并且不影响大肠杆菌细胞，其显然结合到与微管蛋白中的抗肿瘤药物紫杉醇的结合位点相当的区域（Haydon，D. J.，Stokes，N. R.，乌雷河，Galbraith，G.，班尼特，J.M.，布朗，D。R.，贝克，P. J.，巴里宁，V. V.，赖斯，D. W.，Sedelkova，S. E、治愈，J.R.，谢里丹，J.M.，Aiwale，S. T.，Chauhan，P. K.，斯里瓦斯塔瓦，A.，Taneja，A.，柯林斯岛，Errington，J.，和Czaplewski，L. G.（2008）Science 312，16731675）。我们已经发现苯甲酰胺衍生物PC 190723是FtsZ聚合物稳定剂。PC 190723诱导Bs-FtsZ成核组装成单链卷曲原丝和多态凝聚物，包括束、卷曲和环，其形成可以通过不同的溶液条件进行调节。在Bs-FtsZ可逆组装的条件下，PC 190723结合降低了GTdR活性并诱导形成直束和条带，这也在Sa-FtsZ中观察到，但在不敏感的Ec-FtsZ中没有观察到。片段2，6-二氟-3-甲氧基苯甲酰胺也诱导Bs-FtsZ成束。我们建议，聚合物稳定PC 190723抑制体内FtsZ聚合物动力学和细菌分裂。PC 190723对FtsZ的生化作用与微管稳定剂紫杉醇对真核生物结构同源物微管蛋白的作用相似。紫杉醇和PC 190723通过优先结合到每个组装的蛋白质上来稳定聚合物以防止分解。这两种配体是否靶向结构相关的组装开关还有待研究。
Cell division protein FtsZ can form single-stranded filaments with a cooperative behavior by self-switching assembly. Subsequent condensation and bending of FtsZ filaments are important for the formation and constriction of the cytokinetic ring. PC190723 is an effective bactericidal cell division inhibitor that targets FtsZ in the pathogen Staphylococcus aureus and Bacillus subtilis and does not affect Escherichia coli cells, which apparently binds to a zone equivalent to the binding site of the antitumor drug taxol in tubulin (Haydon, D. J., Stokes, N. R., Ure, R., Galbraith, G., Bennett, J. M., Brown, D. R., Baker, P. J., Barynin, V. V., Rice, D. W., Sedelnikova, S. E., Heal, J. R., Sheridan, J. M., Aiwale, S. T., Chauhan, P. K., Srivastava, A., Taneja, A., Collins, I., Errington, J., and Czaplewski, L. G. (2008) Science 312, 16731675). We have found that the benzamide derivative PC190723 is an FtsZ polymer-stabilizing agent. PC190723 induced nucleated assembly of Bs-FtsZ into single-stranded coiled protofilaments and polymorphic condensates, including bundles, coils, and toroids, whose formation could be modulated with different solution conditions. Under conditions for reversible assembly of Bs-FtsZ, PC190723 binding reduced the GTPase activity and induced the formation of straight bundles and ribbons, which was also observed with Sa-FtsZ but not with nonsusceptible Ec-FtsZ. The fragment 2,6-difluoro-3-methoxybenzamide also induced Bs-FtsZ bundling. We propose that polymer stabilization by PC190723 suppresses in vivo FtsZ polymer dynamics and bacterial division. The biochemical action of PC190723 on FtsZ parallels that of the microtubule-stabilizing agent taxol on the eukaryotic structural homologue tubulin. Both taxol and PC190723 stabilize polymers against disassembly by preferential binding to each assembled protein. It is yet to be investigated whether both ligands target structurally related assembly switches.