9ssi

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

spinqualitylabelsall models 9ssi, resolution 1.64Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9ssi is a 1 chain structure with sequence from Streptococcus pneumoniae R6. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.64Å Ligands: CDS, CL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function O70038_STREE Publication Abstract from PubMed 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 beta-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 (<2A) of S. pneumoniae PBP1b cocrystallized with 6 beta-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 beta-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. Structural and Dynamics Analyses of beta-Lactam Inhibition of Streptococcus pneumoniae Penicillin-Binding Protein 1b (PBP1b) Guide Interrogation of Structure-Activity Relationships.,Flanders PL, Gillingham JR, Contreras-Martel C, Dessen A, Carlson EE, Ambrose EA ACS Chem Biol. 2026 Jan 27. doi: 10.1021/acschembio.5c00788. PMID:41589753 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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