Läppchen Tilman, Pinas Victorine A, Hartog Aloysius F, Koomen Gerrit-Jan, Schaffner-Barbero Claudia, Andreu José Manuel, Trambaiolo Daniel, Löwe Jan, Juhem Aurélie, Popov Andrei V, den Blaauwen Tanneke
Van 't Hoff Institute for Molecular Sciences, Bioorganic Chemistry, University of Amsterdam, Nieuwe Achtergracht 129, 1018 WS Amsterdam, The Netherlands.
Chem Biol. 2008 Feb;15(2):189-99. doi: 10.1016/j.chembiol.2007.12.013.
The cytoskeletal proteins, FtsZ and tubulin, play a pivotal role in prokaryotic cell division and eukaryotic chromosome segregation, respectively. Selective inhibitors of the GTP-dependent polymerization of FtsZ could constitute a new class of antibiotics, while several inhibitors of tubulin are widely used in antiproliferative therapy. In this work, we set out to identify selective inhibitors of FtsZ based on the structure of its natural ligand, GTP. We found that GTP analogs with small hydrophobic substituents at C8 of the nucleobase efficiently inhibit FtsZ polymerization, whereas they have an opposite effect on the polymerization of tubulin. The inhibitory activity of the GTP analogs on FtsZ polymerization allowed us to crystallize FtsZ in complex with C8-morpholino-GTP, revealing the binding mode of a GTP derivative containing a nonmodified triphosphate chain.
细胞骨架蛋白FtsZ和微管蛋白分别在原核细胞分裂和真核染色体分离中起关键作用。FtsZ依赖GTP聚合的选择性抑制剂可构成一类新型抗生素，而微管蛋白的几种抑制剂广泛用于抗增殖治疗。在这项研究中，我们着手基于其天然配体GTP的结构来鉴定FtsZ的选择性抑制剂。我们发现，在核苷酸碱基的C8处带有小的疏水取代基的GTP类似物能有效抑制FtsZ聚合，而它们对微管蛋白的聚合有相反的作用。GTP类似物对FtsZ聚合的抑制活性使我们能够使FtsZ与C8-吗啉代-GTP形成复合物结晶，揭示了含有未修饰三磷酸链的GTP衍生物的结合模式。
