8VBW

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

8VBW の概要

• エントリーDOI: 10.2210/pdb8vbw/pdb
• 分子名称: Penicillin-binding protein 1, (4R,5S)-3-({(3S,5S)-5-[(3-carboxyphenyl)carbamoyl]pyrrolidin-3-yl}sulfanyl)-5-[(1S,2R)-1-formyl-2-hydroxypropyl]-4-methyl-4,5-dihydro-1H-pyrrole-2-carboxylic acid (3 entities in total)
• 機能のキーワード: penicillin binding protein 1, peptidoglycan transpeptidase domain, pedestal domain, membrane protein, hydrolase-inhibitor, antibiotic complex, hydrolase/inhibitor, antibiotic
• 由来する生物種: Staphylococcaceae bacterium
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 134243.58

構造登録者

Bon, C.G.,Lee, J.,Caveney, N.A.,Strynadka, N.C.J. (登録日: 2023-12-12, 公開日: 2024-05-01, 最終更新日: 2024-10-23)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.3 Å)