3O86

Crystal structure of AmpC beta-lactamase in complex with a sulfonamide boronic acid inhibitor

3O86 の概要

• エントリーDOI: 10.2210/pdb3o86/pdb
• 関連するPDBエントリー: 3O87 3O88
• 分子名称: Beta-lactamase, {[(benzylsulfonyl)amino]methyl}boronic acid, PHOSPHATE ION, ... (4 entities in total)
• 機能のキーワード: contains alpha helices and a beta sandwich / beta-lactamase-like fold / ampc beta-lactamase, class c, hydrolase, cephalosporinase
• 由来する生物種: Escherichia coli
• 細胞内の位置: Periplasm: P00811
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 79823.91

構造登録者

Eidam, O.,Romagnoli, C.,Karpiak, J.,Shoichet, B.K. (登録日: 2010-08-02, 公開日: 2010-11-03, 最終更新日: 2024-11-20)

主引用文献

Eidam, O.,Romagnoli, C.,Caselli, E.,Babaoglu, K.,Pohlhaus, D.T.,Karpiak, J.,Bonnet, R.,Shoichet, B.K.,Prati, F.
Design, Synthesis, Crystal Structures, and Antimicrobial Activity of Sulfonamide Boronic Acids as beta-Lactamase Inhibitors
J.Med.Chem., 53:7852-7863, 2010

PubMed Abstract: We investigated a series of sulfonamide boronic acids that resulted from the merging of two unrelated AmpC β-lactamase inhibitor series. The new boronic acids differed in the replacement of the canonical carboxamide, found in all penicillin and cephalosporin antibiotics, with a sulfonamide. Surprisingly, these sulfonamides had a highly distinct structure-activity relationship from the previously explored carboxamides, high ligand efficiencies (up to 0.91), and K(i) values down to 25 nM and up to 23 times better for smaller analogues. Conversely, K(i) values were 10-20 times worse for larger molecules than in the carboxamide congener series. X-ray crystal structures (1.6-1.8 Å) of AmpC with three of the new sulfonamides suggest that this altered structure-activity relationship results from the different geometry and polarity of the sulfonamide versus the carboxamide. The most potent inhibitor reversed β-lactamase-mediated resistance to third generation cephalosporins, lowering their minimum inhibitory concentrations up to 32-fold in cell culture.

PubMed: 20945905
DOI: 10.1021/jm101015z

実験手法

X-RAY DIFFRACTION (1.6 Å)