7ATW

Structure of P. aeruginosa PBP3 in complex with a benzoxaborole (Compound 3)

7ATW の概要

• エントリーDOI: 10.2210/pdb7atw/pdb
• 関連するPDBエントリー: 7ATM 7ATO 7ATX 7AU0 7AU1 7AU8 7AU9 7AUB 7AUH
• 分子名称: Peptidoglycan D,D-transpeptidase FtsI, GLYCEROL, 1-Hydroxy-1,3-dihydro-2,1-benzoxaborole-6-carboxylic acid, ... (4 entities in total)
• 機能のキーワード: d, d-transpeptidase, boron-binding, divalency, hydrolase
• 由来する生物種: Pseudomonas aeruginosa
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 58481.28

構造登録者

Newman, H.,Bellini, B.,Dowson, C.G. (登録日: 2020-11-01, 公開日: 2021-08-11, 最終更新日: 2024-11-20)

主引用文献

Newman, H.,Krajnc, A.,Bellini, D.,Eyermann, C.J.,Boyle, G.A.,Paterson, N.G.,McAuley, K.E.,Lesniak, R.,Gangar, M.,von Delft, F.,Brem, J.,Chibale, K.,Schofield, C.J.,Dowson, C.G.
High-Throughput Crystallography Reveals Boron-Containing Inhibitors of a Penicillin-Binding Protein with Di- and Tricovalent Binding Modes.
J.Med.Chem., 64:11379-11394, 2021

PubMed Abstract: The effectiveness of β-lactam antibiotics is increasingly compromised by β-lactamases. Boron-containing inhibitors are potent serine-β-lactamase inhibitors, but the interactions of boron-based compounds with the penicillin-binding protein (PBP) β-lactam targets have not been extensively studied. We used high-throughput X-ray crystallography to explore reactions of a boron-containing fragment set with the PBP3 (PaPBP3). Multiple crystal structures reveal that boronic acids react with PBPs to give tricovalently linked complexes bonded to Ser294, Ser349, and Lys484 of PaPBP3; benzoxaboroles react with PaPBP3 via reaction with two nucleophilic serines (Ser294 and Ser349) to give dicovalently linked complexes; and vaborbactam reacts to give a monocovalently linked complex. Modifications of the benzoxaborole scaffold resulted in a moderately potent inhibition of PaPBP3, though no antibacterial activity was observed. Overall, the results further evidence the potential for the development of new classes of boron-based antibiotics, which are not compromised by β-lactamase-driven resistance.

PubMed: 34337941
DOI: 10.1021/acs.jmedchem.1c00717

実験手法

X-RAY DIFFRACTION (1.44 Å)