8VBV

Structure of the monofunctional Staphylococcus aureus PBP1 in its beta-lactam (Cephalexin) inhibited form

Summary for 8VBV

• Entry DOI: 10.2210/pdb8vbv/pdb
• Descriptor: Penicillin-binding protein 1, (2S)-2-[(1R)-1-{[(2R)-2-amino-2-phenylacetyl]amino}-2-oxoethyl]-5-methyl-3,6-dihydro-2H-1,3-thiazine-4-carboxylic acid (3 entities in total)
• Functional Keywords: penicillin binding protein 1, peptidoglycan transpeptidase domain, pedestal domain, membrane protein, hydrolase-inhibitor, antibiotic complex, hydrolase/inhibitor, antibiotic
• Biological source: Staphylococcaceae bacterium
• Total number of polymer chains: 2
• Total formula weight: 133987.33

Authors

Bon, C.G.,Lee, J.,Caveney, N.A.,Strynadka, N.C.J. (deposition date: 2023-12-12, release date: 2024-05-01, Last modification date: 2024-10-30)

Primary citation

Bon, C.G.,Grigg, J.C.,Lee, J.,Robb, C.S.,Caveney, N.A.,Eltis, L.D.,Strynadka, N.C.J.
Structural and kinetic analysis of the monofunctional Staphylococcus aureus PBP1.
J.Struct.Biol., 216:108086-108086, 2024

PubMed Abstract: Staphylococcus aureus, an ESKAPE pathogen, is a major clinical concern due to its pathogenicity and manifold antimicrobial resistance mechanisms. The commonly used β-lactam antibiotics target bacterial penicillin-binding proteins (PBPs) and inhibit crosslinking of peptidoglycan strands that comprise the bacterial cell wall mesh, initiating a cascade of effects leading to bacterial cell death. S. aureus PBP1 is involved in synthesis of the bacterial cell wall during division and its presence is essential for survival of both antibiotic susceptible and resistant S. aureus strains. Here, we present X-ray crystallographic data for S. aureus PBP1 in its apo form as well as acyl-enzyme structures with distinct classes of β-lactam antibiotics representing the penicillins, carbapenems, and cephalosporins, respectively: oxacillin, ertapenem and cephalexin. Our structural data suggest that the PBP1 active site is readily accessible for substrate, with little conformational change in key structural elements required for its covalent acylation of β-lactam inhibitors. Stopped-flow kinetic analysis and gel-based competition assays support the structural observations, with even the weakest performing β-lactams still having comparatively high acylation rates and affinities for PBP1. Our structural and kinetic analysis sheds insight into the ligand-PBP interactions that drive antibiotic efficacy against these historically useful antimicrobial targets and expands on current knowledge for future drug design and treatment of S. aureus infections.

PubMed: 38527711
DOI: 10.1016/j.jsb.2024.108086

Experimental method

X-RAY DIFFRACTION (2.4 Å)