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

细菌细胞分裂被认为是该王国中最高度保守的过程之一。在分裂体的其他下游组分以高度协调的方式组装之前，FtsA（细菌肌动蛋白）将FtsZ（细菌微管蛋白）的Z环锚在细胞质膜的内侧。这些蛋白质中的两种是ATP酶FtsE和多位膜蛋白FtsX，它们作为早期分裂体组装的一部分组装，这是后续进一步下游组件组装所需的。除此之外，FtsEX复合物已在子细胞分离期间的肽聚糖（PG）分解中实施。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还没有得到很好的理解，并可能提供关键的洞察未来的化疗策略，将管理下一代抗生素的发展。我们建议在革兰氏阳性菌肺炎链球菌中研究该系统;肺炎链球菌是一种机会致病菌，每年造成约6000例死亡，主要发生在老年人和5岁以下儿童中。最近，S. pneumoniae PcsB的晶体结构已经解析，揭示了V形构象，含有CHAPS结构域的活性位点位于卷曲螺旋结构域附近。基于FtsX和EnvC在E.在大肠杆菌中，PcsB需要经历构象变化才能被激活。这可能是促进ATP酶的作用FtsE，虽然分子机制尚不清楚，这是我们建议在这个项目中研究的部分。

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.