3IOF

Crystal structure of CphA N220G mutant with inhibitor 10a

3IOF の概要

• エントリーDOI: 10.2210/pdb3iof/pdb
• 関連するPDBエントリー: 1X8G 1x8h 1x8i 3F9O 3FAI 3IOG
• 分子名称: Beta-lactamase, ZINC ION, bis(1-methylethyl) [2-(sulfanylmethyl)phenyl]phosphonate, ... (6 entities in total)
• 機能のキーワード: hydrolase, antibiotic resistance, metal-binding
• 由来する生物種: Aeromonas hydrophila
• 細胞内の位置: Periplasm : P26918
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 26754.43

構造登録者

Delbruck, H.,Bebrone, C.,Hoffmann, K.M.V. (登録日: 2009-08-14, 公開日: 2010-06-23, 最終更新日: 2023-11-01)

主引用文献

Lassaux, P.,Hamel, M.,Gulea, M.,Delbruck, H.,Mercuri, P.S.,Horsfall, L.,Dehareng, D.,Kupper, M.,Frere, J.-M.,Hoffmann, K.,Galleni, M.,Bebrone, C.
Mercaptophosphonate Compounds as Broad-Spectrum Inhibitors of the Metallo-beta-lactamases
J.Med.Chem., 53:4862-4876, 2010

PubMed Abstract: Although commercialized inhibitors of active site serine beta-lactamases are currently used in coadministration with antibiotic therapy, no clinically useful inhibitors of metallo-beta-lactamases (MBLs) have yet been discovered. In this paper, we investigated the inhibitory effect of mercaptophosphonate derivatives against the three subclasses of MBLs (B1, B2, and B3). All 14 tested mercaptophosphonates, with the exception of 1a, behaved as competitive inhibitors for the three subclasses. Apart from 13 and 21, all the mercaptophosphonates tested exhibit a good inhibitory effect on the subclass B2 MBL CphA with low inhibition constants (K(i) < 15 muM). Interestingly, compound 18 turned out to be a potent broad spectrum MBL inhibitor. The crystallographic structures of the CphA-10a and CphA-18 complexes indicated that the sulfur atom of 10a and the phosphonato group of 18 interact with the Zn(2+) ion, respectively. Molecular modeling studies of the interactions between compounds 10a and 18 and the VIM-4 (B1), CphA (B2), and FEZ-1 (B3) enzymes brought to light different binding modes depending on the enzyme and the inhibitor, consistent with the crystallographic structures.

PubMed: 20527888
DOI: 10.1021/jm100213c

実験手法

X-RAY DIFFRACTION (1.44 Å)