3LCE

Crystal Structure of Oxa-10 Beta-Lactamase Covalently Bound to Cyclobutanone Beta-Lactam Mimic

3LCE の概要

• エントリーDOI: 10.2210/pdb3lce/pdb
• 分子名称: Beta-lactamase OXA-10, GLYCEROL, (1S,3S,4S,5S)-7,7-dichloro-3-methoxy-2-thiabicyclo[3.2.0]heptan-6-one-4-carboxylic acid, ... (5 entities in total)
• 機能のキーワード: beta-lactamase, beta-lactamase inhibitor, beta-lactam mimic, cyclobutanone, hemiketal, antibiotic resistance, disulfide bond, hydrolase, plasmid, transposable element
• 由来する生物種: Pseudomonas aeruginosa
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 112014.38

構造登録者

Gretes, M.,Strynadka, N.C.J. (登録日: 2010-01-10, 公開日: 2010-03-09, 最終更新日: 2023-11-22)

主引用文献

Johnson, J.W.,Gretes, M.,Goodfellow, V.J.,Marrone, L.,Heynen, M.L.,Strynadka, N.C.,Dmitrienko, G.I.
Cyclobutanone Analogues of beta-Lactams Revisited: Insights into Conformational Requirements for Inhibition of Serine- and Metallo-beta-Lactamases.
J.Am.Chem.Soc., 132:2558-2560, 2010

PubMed Abstract: The most important mode of bacterial resistance to beta-lactam antibiotics is the expression of beta-lactamases. New cyclobutanone analogues of penams and penems have been prepared and evaluated for inhibition of class A, B, C, and D beta-lactamases. Inhibitors which favor conformations in which the C4 carboxylate is equatorial were found to be more potent than those in which the carboxylate is axial, and molecular modeling studies with enzyme-inhibitor complexes indicate that an equatorial orientation of the carboxylate is required for binding to beta-lactamases. An X-ray structure of OXA-10 complexed with a cyclobutanone confirms that a serine hemiketal is formed in the active site and that the inhibitor adopts the exo envelope. An unsaturated penem analogue was also found to enhance the potency of meropenem against carbapenem-resistant MBL-producing strains of Chryseobacterium meningosepticum and Stenotrophomonas maltophilia. These cyclobutanones represent the first type of reversible inhibitors to show moderate (low micromolar) inhibition of both serine- and metallo-beta-lactamases and should be considered for further development into practical inhibitors.

PubMed: 20141132
DOI: 10.1021/ja9086374

実験手法

X-RAY DIFFRACTION (2 Å)