Screening and Protein Sciences, Merck Research Laboratories, West Point, Pennsylvania 19486, United States.
J Am Chem Soc. 2012 Aug 1;134(30):12342-5. doi: 10.1021/ja303564a. Epub 2012 Jul 20.
The cooperative assembly of FtsZ, the prokaryotic homologue of tubulin, plays an essential role in cell division. FtsZ is a potential drug target, as illustrated by the small-molecule cell-cycle inhibitor and antibacterial agent PC190723 that targets FtsZ. We demonstrate that PC190723 negatively modulates Staphylococcus aureus FtsZ polymerization cooperativity as reflected in polymerization at lower concentrations without a defined critical concentration. The crystal structure of the S. aureus FtsZ-PC190723 complex shows a domain movement that would stabilize the FtsZ protofilament over the monomeric state, with the conformational change mediated from the GTP-binding site to the C-terminal domain via helix 7. Together, the results reveal the molecular mechanism of FtsZ modulation by PC190723 and a conformational switch to the high-affinity state that enables polymer assembly.
FtsZ 的合作组装，原核生物微管蛋白的同源物，在细胞分裂中起着至关重要的作用。FtsZ 是一个潜在的药物靶点，小分子细胞周期抑制剂和抗菌剂 PC190723 就是针对 FtsZ 的。我们证明 PC190723 负调节金黄色葡萄球菌 FtsZ 聚合协同性，表现在较低浓度下聚合而没有明确的临界浓度。金黄色葡萄球菌 FtsZ-PC190723 复合物的晶体结构显示出一个结构域运动，这将稳定 FtsZ 原丝在单体状态下，构象变化通过从 GTP 结合位点到 C 端结构域的螺旋 7 进行介导。总之，这些结果揭示了 PC190723 对 FtsZ 调节的分子机制和构象转换到高亲和力状态，从而实现聚合物组装。
