9SSE | pdb_00009sse

Structural and Dynamics Analyses of beta-Lactam Inhibition of Streptococcus pneumoniae Penicillin-Binding Protein 1b (PBP1b) Guide Interrogation of Structure-Activity Relationships.

(2026) ACS Chem Biol 

• PubMed: 41589753 Search on PubMed
• 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.

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Organizational Affiliation: 
• Department of Medicinal Chemistry, University of Minnesota, 208 Harvard Street SE, Minneapolis, Minnesota 55454, United States.
Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, 321 Church St SE, Minneapolis, Minnesota 55454, United States.
Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale (IBS), Grenoble F-38044, France.
Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States.
Department of Pharmacology, University of Minnesota, 321 Church St SE, Minneapolis, Minnesota 55454, United States.
Minnesota Supercomputing Institute for Advanced Computational Research, University of Minnesota, 117 Pleasant St SE, Minneapolis, Minnesota 55455, United States.
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