2 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
Structural Basis of Small-Molecule Aggregate Induced Inhibition of a Protein–Protein Interaction
A prevalent observation
in high-throughput screening and drug discovery
programs is the inhibition of protein function by small-molecule compound
aggregation. Here, we present the X-ray structural description of
aggregation-based inhibition of a protein–protein interaction
involving tumor necrosis factor α (TNFα). An ordered conglomerate
of an aggregating small-molecule inhibitor (JNJ525) induces a quaternary
structure switch of TNFα that inhibits the protein–protein
interaction between TNFα and TNFα receptors. SPD-304 may
employ a similar mechanism of inhibition