Download MendeleyStructural and Dynamics Analyses of beta-Lactam Inhibition of Streptococcus pneumoniae Penicillin-Binding Protein 1b (PBP1b) Guide Interrogation of Structure-Activity Relationships.
Flanders, P.L., Gillingham, J.R., Contreras-Martel, C., Dessen, A., Carlson, E.E., Ambrose, E.A.(2026) ACS Chem Biol
- PubMed: 41589753
- DOI: https://doi.org/10.1021/acschembio.5c00788
- Primary Citation of Related Structures:
7ZUH, 9SSD, 9SSE, 9SSF, 9SSG, 9SSH, 9SSI - PubMed Abstract:
The Gram-positive pathogen Streptococcus pneumoniae , like the majority of bacteria, contains a peptidoglycan-based cell wall whose structure is highly dependent on the action of penicillin-binding proteins (PBPs). While the β-lactam antibiotics have been employed as an antimicrobial strategy for nearly a century, much remains unclear about how inhibitor structure informs potency and PBP isoform selectivity. Here, we obtained high-resolution structures (<2Å) of S. pneumoniae PBP1b cocrystallized with 6 β-lactams. Surprisingly, 2 structures feature a noncanonical conformation of the covalent "acyl-enzyme complex." To clarify how protein-ligand interactions mediate inhibitor binding, we applied molecular modeling and molecular mechanics-based dynamics analyses. Our analyses illustrate how seemingly minimal changes to inhibitor structure modulate β-lactam binding mode and inhibitor potency, as described by the metric k inact / K I . Furthermore, we demonstrate that persistent interaction in the covalent acyl-enzyme complex between the inhibitor carboxylate and a highly conserved three-residue motif is not fully predictive of k inact / K I for PBP1b. In silico modeling suggests that the noncovalent preacyl complex may leverage this interaction, but a postacylation change in ligand conformation may accompany acylation in some inhibitors. The elucidation of key PBP1b ligand-receptor interactions pre- and postacylation will inform the rational design of novel PBP inhibitors and probes.
- Department of Medicinal Chemistry, University of Minnesota, 208 Harvard Street SE, Minneapolis, Minnesota 55454, United States.
Organizational Affiliation:
