Structural & Biochemical Characterisation of the Streptococcus pneumoniae Early-Stage Division Complex, FtsEX-PcsB.

结构性

• 批准号: 2264827
• 金额: --
• 依托单位: University of Warwick
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2264827
• 关键词: Structural; Biochemical; Characterisation; Streptococcus; pneumoniae

Bacterial cell division is seen as one of the most highly conserved processes that occurs in that kingdom. FtsA (bacterial actin) works to anchor the Z-ring of FtsZ (bacterial tubulin) to the inner side of the cytoplasmic membrane, before other downstream components of the Divisome assemble in a highly coordinated manner. Two of these proteins are the ATPase FtsE, and the polytopic membrane protein FtsX that assemble as part of the early-stage Divisome assembly, which are required for subsequent assembly of further downstream components. Further to this, the FtsEX complex has been implemented in a peptidoglycan (PG) breakdown during daughter cell separation. To facilitate this, FtsX associates with the probable PG hydrolase, PcsB. These interaction as well as the control mechanisms are not well understood, and may provide crucial insight into future chemotherapeutic strategies that will govern the development of next-generation antibiotics. We propose to study this system in the Gram-positive organism, Streptococcus pneumoniae; an opportunistic pathogen responsible for around 6000 deaths per year, predominantly in the elderly and children under 5. Recently, the S. pneumoniae PcsB crystal structure has been solved, revealing a V-shaped conformation, the active site containing CHAPS domain residing close to the coiled-coil domain. Based on the homologous interaction between FtsX and EnvC in E. coli, PcsB will need to undergo a conformational change in order to become activated. This may be facilitated by the ATPase action of FtsE, though the molecular mechanisms are unclear; which is in part what we propose to study in this project.

细菌细胞分裂被视为该王国中发生的最高度保守的过程之一。 FtsA（细菌肌动蛋白）的作用是将 FtsZ（细菌微管蛋白）的 Z 环锚定在细胞质膜的内侧，然后 Divisome 的其他下游组件以高度协调的方式组装。其中两种蛋白质是 ATPase FtsE 和多胞膜蛋白 FtsX，它们作为早期 Divisome 组装的一部分进行组装，这是后续组装进一步下游组件所必需的。此外，FtsEX 复合物已在子细胞分离过程中的肽聚糖 (PG) 分解中得到应用。为了促进这一点，FtsX 与可能的 PG 水解酶 PcsB 结合。这些相互作用以及控制机制尚不清楚，但可能为未来控制下一代抗生素开发的化疗策略提供重要的见解。我们建议在革兰氏阳性菌肺炎链球菌中研究这个系统；一种机会性病原体，每年造成约 6000 人死亡，主要是老年人和 5 岁以下儿童。最近，肺炎链球菌 PcsB 晶体结构已被解析，揭示了 V 形构象，含有 CHAPS 结构域的活性位点靠近卷曲螺旋域。基于大肠杆菌中 FtsX 和 EnvC 之间的同源相互作用，PcsB 需要经历构象变化才能被激活。尽管分子机制尚不清楚，但 FtsE 的 ATP 酶作用可能促进了这一过程。这是我们建议在这个项目中研究的部分内容。