1 research outputs found
Mechanism of Action of the Cell-Division Inhibitor PC190723: Modulation of FtsZ Assembly Cooperativity
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 <i>Staphylococcus aureus</i> FtsZ polymerization cooperativity as reflected in polymerization
at lower concentrations without a defined critical concentration.
The crystal structure of the <i>S. aureus</i> 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