Probing FtsZ and tubulin with C8-substituted GTP analogs reveals differences in their nucleotide binding sites.
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.
Läppchen
Tilman
T
Van 't Hoff Institute for Molecular Sciences, Bioorganic Chemistry, University of Amsterdam, Nieuwe Achtergracht 129, 1018 WS Amsterdam, The Netherlands.
Pinas
Victorine A
VA
Hartog
Aloysius F
AF
Koomen
Gerrit-Jan
GJ
Schaffner-Barbero
Claudia
C
Andreu
José Manuel
JM
Trambaiolo
Daniel
D
Löwe
Jan
J
Juhem
Aurélie
A
Popov
Andrei V
AV
den Blaauwen
Tanneke
T
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
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