近日,英国诺丁汉大学生物分子科学中心研究人员表示,他们发现了对付大肠杆菌菌株的新线索。研究结果发表在了《生物化学期刊》(Journal of Biological Chemistry)上。
研究人员指明了如何使“细菌素”——能够杀死其他细菌菌株的物质——进入细菌细胞进而杀死它,以及如何让大肠杆菌产生的大肠杆菌素A有针对性地到另一个细胞蛋白(TolA)中创建一个新的“特洛伊木马”武器,并最终从内部杀死该细菌细胞。这项研究对于了解分子如何穿透细菌细胞的防御有重要的意义。
目前,大肠杆菌菌株造成的感染的数量比耐甲氧西林金黄色葡萄球菌和难辨梭菌两者加起来还多,并且对常规治疗方法的抗药性越来越强。因此,利用细菌的毒性来打击该细菌将是未来的发展方向。该新研究探讨了大肠杆菌素的物理互动过程,研究人员发现大肠杆菌素A与TolA能够在一个相对面积较小的地区相互作用,这个结合区域强调了分子间的基本互动,并可以保证复杂的相互作用的稳定。研究人员表示,有足够的证据表明,大肠杆菌素A和TolA的结合能够在很大程度上影响细菌细胞的健康。
该研究领头人Christopher Penfold表示,通过这项研究,最终还可能设计出小的新型人工合成化合物,引导出潜在的抗菌疗法,最终阻止TolA的自然功能来消除细胞的死亡和感染。
但是,研究者们还发现即使大肠杆菌素具有良好的抗菌活性,但目前仍然很难将它们作为潜在的新的抗生素被投入使用。主要因为大肠杆菌素是大的蛋白质分子,会激活人体的免疫反应,而在下一次的大肠杆菌素被用于治疗时会成为抗体。(生物谷Bioon.com)
doi:10.1074/jbc.M112.342246
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Structural Evidence That Colicin A Protein Binds to a Novel Binding Site of TolA Protein in Escherichia coli Periplasm*
Chan Li?,1,2, Ying Zhang?,1, Mireille Vankemmelbeke?, Oliver Hecht§, Fadilah Sfouq Aleanizy?, Colin Macdonald§, Geoffrey R. Moore§, Richard James? and Christopher N. Penfold?,3
The Tol assembly of proteins is an interacting network of proteins located in the Escherichia coli cell envelope that transduces energy and contributes to cell integrity. TolA is central to this network linking the inner and outer membranes by interactions with TolQ, TolR, TolB, and Pal. Group A colicins, such as ColA, parasitize the Tol network through interactions with TolA and/or TolB to facilitate translocation through the cell envelope to reach their cytotoxic site of action. We have determined the first structure of the C-terminal domain of TolA (TolAIII) bound to an N-terminal ColA polypeptide (TA53–107). The interface region of the TA53–107-TolAIII complex consists of polar contacts linking residues Arg-92 to Arg-96 of ColA with residues Leu-375–Pro-380 of TolA, which constitutes a β-strand addition commonly seen in more promiscuous protein-protein contacts. The interface region also includes three cation-π interactions (Tyr-58–Lys-368, Tyr-90–Lys-379, Phe-94–Lys-396), which have not been observed in any other colicin-Tol protein complex. Mutagenesis of the interface residues of ColA or TolA revealed that the effect on the interaction was cumulative; single mutations of either partner had no effect on ColA activity, whereas mutations of three or more residues significantly reduced ColA activity. Mutagenesis of the aromatic ring component of the cation-π interacting residues showed Tyr-58 of ColA to be essential for the stability of complex formation. TA53–107 binds on the opposite side of TolAIII to that used by g3p, ColN, or TolB, illustrating the flexible nature of TolA as a periplasmic hub protein