Abstract
The mechanism of the antibiotic molecule A22 is yet to be clearly understood. In a previous study, we carried out molecular dynamics simulations of a monomer of the bacterial actin-like MreB in complex with different nucleotides and A22, and suggested that A22 impedes the release of Pi from the active site of MreB after the hydrolysis of ATP, resulting in filament instability. On the basis of the suggestion that Pi release occurs on a similar timescale to polymerization and that polymerization can occur in the absence of nucleotides, we sought in this study to investigate a hypothesis that A22 impedes the conformational change in MreB that is required for polymerization through molecular dynamics simulations of the MreB protofilament in the apo, ATP+, and ATP-A22+ states. We suggest that A22 inhibits MreB in part by antagonizing the ATP-induced structural changes required for polymerization. Our data give further insight into the polymerization/depolymerization dynamics of MreB and the mechanism of A22.
Highlights
The bacterial actin-like MreB forms the cytoskeleton network, and is involved in several life processes of rod-shaped bacteria [1,2,3,4,5,6,7,8,9,10]
In a previous study [14], we carried out molecular dynamics (MD) simulations of monomeric bacterial actin-like MreB in complex with different nucleotides (NTs) and A22, and suggested that A22 impedes the release of Pi from the active site of MreB after the hydrolysis of ATP resulting in filament instability
On the basis of the observations we made [14], the fact that Pi release occurs on a similar timescale to polymerization [15,16,17], and that polymerization can occur in the absence of NTs [18], we proposed a hypothesis that A22 interferes with the conformational change in MreB that is required
Summary
The bacterial actin-like MreB forms the cytoskeleton network, and is involved in several life processes of rod-shaped bacteria [1,2,3,4,5,6,7,8,9,10]. MreB polymerizes into filaments which are made of two straight and antiparallel strands, unlike the two twisted and parallel strands of eukaryotic actin [11]. To form a single filament, adjacent monomeric chains of MreB interact longitudinally at the intraprotofilament interfaces (Figure 1b). The polymerization of MreB involves both single filament and double filament formation
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