3LCE
Crystal Structure of Oxa-10 Beta-Lactamase Covalently Bound to Cyclobutanone Beta-Lactam Mimic
Summary for 3LCE
| Entry DOI | 10.2210/pdb3lce/pdb |
| Descriptor | 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) |
| Functional Keywords | beta-lactamase, beta-lactamase inhibitor, beta-lactam mimic, cyclobutanone, hemiketal, antibiotic resistance, disulfide bond, hydrolase, plasmid, transposable element |
| Biological source | Pseudomonas aeruginosa |
| Total number of polymer chains | 4 |
| Total formula weight | 112014.38 |
| Authors | Gretes, M.,Strynadka, N.C.J. (deposition date: 2010-01-10, release date: 2010-03-09, Last modification date: 2023-11-22) |
| Primary citation | 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 Cited by 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: 20141132DOI: 10.1021/ja9086374 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
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