9SSF

PENICILLIN-BINDING PROTEIN 1B (PBP-1B) in complex with Methicillin - Streptococcus pneumoniae R6

Summary for 9SSF

• Entry DOI: 10.2210/pdb9ssf/pdb
• Related: 9SSD 9SSE 9SSG 9SSH 9SSI
• Descriptor: Penicillin-binding protein 1B, (2R,4S)-2-[(1R)-1-{[(2,6-dimethoxyphenyl)carbonyl]amino}-2-oxoethyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: cell wall, peptidoglycan synthesis enzyme, infection, drug-binding protein, antibiotics, transferase
• Biological source: Streptococcus pneumoniae R6
• Total number of polymer chains: 1
• Total formula weight: 55319.18

Authors

Flanders, P.L.,Gillingham, J.R.,Contreras-Martel, C.,Dessen, A.,Carlson, E.E.,Ambrose, E.A. (deposition date: 2025-09-25, release date: 2026-02-18)

Primary citation

Flanders, P.L.,Gillingham, J.R.,Contreras-Martel, C.,Dessen, A.,Carlson, E.E.,Ambrose, E.A.
Structural and Dynamics Analyses of beta-Lactam Inhibition of Streptococcus pneumoniae Penicillin-Binding Protein 1b (PBP1b) Guide Interrogation of Structure-Activity Relationships.
Acs Chem.Biol., 2026

PubMed Abstract: The Gram-positive pathogen , 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 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 /. 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 / for PBP1b. 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.

PubMed: 41589753
DOI: 10.1021/acschembio.5c00788

Experimental method

X-RAY DIFFRACTION (1.931 Å)