Bacteria digest their cell wall after exposure to antibiotics like penicillin, and endopeptidases (EPs) are among the proteins that catalyze this digestion. Mark Saper, his former student Aaron Kelley, and their collaborators report crystal structures of the LysM/M23 family peptidase ShyA, the primary EP of the cholera pathogen Vibrio cholerae. Their data suggest that ShyA assumes two drastically different conformations: a more open form that allows for substrate binding and a closed form, which they predicted to be catalytically inactive. Mutations expected to promote the open conformation led to enhanced activity in vitro and in vivo, and these results were recapitulated in EPs from the divergent pathogens Neisseria gonorrheae and Escherichia coli. The researchers propose that LysM/M23 EPs are regulated via release of the inhibitory Domain 1 from the M23 active site, likely through conformational rearrangement in vivo. This mechanism of EP regulation in gram-negative pathogens could be exploited for the development of antibiotics that activate cell wall digestion by EPs.
Read the article in PNAS HERE.