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 Staphylococcus aureus FtsZ polymerization cooperativity as reflected in polymerization at lower concentrations without a defined critical concentration. The crystal structure of the S. aureus 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.
Screening and Protein Sciences, Merck Research Laboratories, West Point, Pennsylvania 19486, United States.
Nathaniel L
NL
Elsen
Jun
J
Lu
Gopal
G
Parthasarathy
John C
JC
Reid
Sujata
S
Sharma
Stephen M
SM
Soisson
Kevin J
KJ
Lumb
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D062105:Molecular Docking Simulation; D011487:Protein Conformation / Q000187:drug effects*; D017434:Protein Structure, Tertiary / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D003598:Cytoskeletal Proteins; C071525:FtsZ protein, Bacteria; C531944:PC190723; D011725:Pyridines; D013844:Thiazoles