title: Probing FtsZ and tubulin with C8-substituted GTP analogs reveals differences in their nucleotide binding sites.
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.
authors.affiliation: Van 't Hoff Institute for Molecular Sciences, Bioorganic Chemistry, University of Amsterdam, Nieuwe Achtergracht 129, 1018 WS Amsterdam, The Netherlands.
authors.forename: Tilman
authors.initials: T
authors.lastname: Läppchen
authors.forename: Victorine A
authors.initials: VA
authors.lastname: Pinas
authors.forename: Aloysius F
authors.initials: AF
authors.lastname: Hartog
authors.forename: Gerrit-Jan
authors.initials: GJ
authors.lastname: Koomen
authors.forename: Claudia
authors.initials: C
authors.lastname: Schaffner-Barbero
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Andreu
authors.forename: Daniel
authors.initials: D
authors.lastname: Trambaiolo
authors.forename: Jan
authors.initials: J
authors.lastname: Löwe
authors.forename: Aurélie
authors.initials: A
authors.lastname: Juhem
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Popov
authors.forename: Tanneke
authors.initials: T
authors.lastname: den Blaauwen
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism*; D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000378:metabolism*; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000031:analogs & derivatives* / Q000378:metabolism*; D006868:Hydrolysis; D011108:Polymers / Q000378:metabolism; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*; D050257:Tubulin Modulators / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D003598:Cytoskeletal Proteins; C071525:FtsZ protein, Bacteria; D011108:Polymers; D014404:Tubulin; D050257:Tubulin Modulators; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D020558:GTP Phosphohydrolases