7ZUH

PENICILLIN-BINDING PROTEIN 1B (PBP-1B) Streptococcus pneumoniae R6

This is a non-PDB format compatible entry.

Summary for 7ZUH

• Entry DOI: 10.2210/pdb7zuh/pdb
• Descriptor: Penicillin-binding protein 1b, MAGNESIUM ION, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: cell wall, peptidoglycan synthesis enzyme, infection, drug-binding protein, lactam antibiotics, transferase
• Biological source: Streptococcus pneumoniae R6
• Total number of polymer chains: 1
• Total formula weight: 90371.86

Authors

Flanders, P.L.,Contreras-Martel, C.,Martins, A.,Brown, N.W.,Shirley, J.D.,Nauta, K.M.,Dessen, A.,Carlson, E.E.,Ambrose, E.A. (deposition date: 2022-05-12, release date: 2022-11-02, Last modification date: 2024-01-31)

Primary citation

Flanders, P.L.,Contreras-Martel, C.,Brown, N.W.,Shirley, J.D.,Martins, A.,Nauta, K.N.,Dessen, A.,Carlson, E.E.,Ambrose, E.A.
Combined Structural Analysis and Molecular Dynamics Reveal Penicillin-Binding Protein Inhibition Mode with beta-Lactones.
Acs Chem.Biol., 17:3110-3120, 2022

PubMed Abstract: β-Lactam antibiotics comprise one of the most widely used therapeutic classes to combat bacterial infections. This general scaffold has long been known to inhibit bacterial cell wall biosynthesis by inactivating penicillin-binding proteins (PBPs); however, bacterial resistance to β-lactams is now widespread, and new strategies are urgently needed to target PBPs and other proteins involved in bacterial cell wall formation. A key requirement in the identification of strategies to overcome resistance is a deeper understanding of the roles of the PBPs and their associated proteins during cell growth and division, such as can be obtained with the use of selective chemical probes. Probe development has typically depended upon known PBP inhibitors, which have historically been thought to require a negatively charged moiety that mimics the C-terminus of the PBP natural peptidoglycan substrate, d-Ala-d-Ala. However, we have identified a new class of β-lactone-containing molecules that interact with PBPs, often in an isoform-specific manner, and do not incorporate this C-terminal mimetic. Here, we report a series of structural biology experiments and molecular dynamics simulations that we utilized to evaluate specific binding modes of this novel PBP inhibitor class. In this work, we obtained <2 Å resolution X-ray structures of four β-lactone probes bound to PBP1b from . Despite their diverging recognition modes beyond the site of covalent modification, these four probes all efficiently labeled PBP1b, as well as other PBPs from . . From these structures, we analyzed protein-ligand interactions and characterized the β-lactone-bound active sites using mutagenesis and molecular dynamics. Our approach has clarified the dynamic interaction profile in this series of ligands, expanding the understanding of PBP inhibitor binding.

PubMed: 36173746
DOI: 10.1021/acschembio.2c00503

Experimental method

X-RAY DIFFRACTION (1.467 Å)