Probing FtsZ and tubulin with C8-substituted GTP analogs reveals differences in their nucleotide binding sites

Chem Biol. 2008 Feb;15(2):189-99. doi: 10.1016/j.chembiol.2007.12.013.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacterial Proteins / chemistry
  • Bacterial Proteins / metabolism*
  • Binding, Competitive
  • Crystallography, X-Ray
  • Cytoskeletal Proteins / chemistry
  • Cytoskeletal Proteins / metabolism*
  • GTP Phosphohydrolases / metabolism
  • Guanosine Diphosphate / metabolism
  • Guanosine Triphosphate / analogs & derivatives*
  • Guanosine Triphosphate / metabolism*
  • Hydrolysis
  • Polymers / metabolism
  • Tubulin / chemistry
  • Tubulin / metabolism*
  • Tubulin Modulators / metabolism

Substances

  • Bacterial Proteins
  • Cytoskeletal Proteins
  • FtsZ protein, Bacteria
  • Polymers
  • Tubulin
  • Tubulin Modulators
  • Guanosine Diphosphate
  • Guanosine Triphosphate
  • GTP Phosphohydrolases

Associated data

  • PDB/2R75