4GZB

Crystal structure of native AmpC beta-lactamase from Pseudomonas aeruginosa PAO1

Summary for 4GZB

• Entry DOI: 10.2210/pdb4gzb/pdb
• Related: 4HBT 4HBU 4HEF
• Descriptor: Beta-lactamase, 1,2-ETHANEDIOL (3 entities in total)
• Functional Keywords: beta-lactamase fold, hydrolase, antibiotic resistance
• Biological source: Pseudomonas aeruginosa
• Cellular location: Periplasm (By similarity): P24735
• Total number of polymer chains: 1
• Total formula weight: 40786.03

Authors

Benvenuti, M.,De Luca, F.,Docquier, J.D.,Mangani, S. (deposition date: 2012-09-06, release date: 2013-04-10, Last modification date: 2023-11-08)

Primary citation

Lahiri, S.D.,Mangani, S.,Durand-Reville, T.,Benvenuti, M.,De Luca, F.,Sanyal, G.,Docquier, J.D.
Structural insight into potent broad-spectrum inhibition with reversible recyclization mechanism: avibactam in complex with CTX-M-15 and Pseudomonas aeruginosa AmpC beta-lactamases
Antimicrob.Agents Chemother., 57:2496-2505, 2013

PubMed Abstract: Although β-lactams have been the most effective class of antibacterial agents used in clinical practice for the past half century, their effectiveness on Gram-negative bacteria has been eroded due to the emergence and spread of β-lactamase enzymes that are not affected by currently marketed β-lactam/β-lactamase inhibitor combinations. Avibactam is a novel, covalent, non-β-lactam β-lactamase inhibitor presently in clinical development in combination with either ceftaroline or ceftazidime. In vitro studies show that avibactam may restore the broad-spectrum activity of cephalosporins against class A, class C, and some class D β-lactamases. Here we describe the structures of two clinically important β-lactamase enzymes bound to avibactam, the class A CTX-M-15 extended-spectrum β-lactamase and the class C Pseudomonas aeruginosa AmpC β-lactamase, which together provide insight into the binding modes for the respective enzyme classes. The structures reveal similar binding modes in both enzymes and thus provide a rationale for the broad-spectrum inhibitory activity of avibactam. Identification of the key residues surrounding the binding pocket allows for a better understanding of the potency of this scaffold. Finally, avibactam has recently been shown to be a reversible inhibitor, and the structures provide insights into the mechanism of avibactam recyclization. Analysis of the ultra-high-resolution CTX-M-15 structure suggests how the deacylation mechanism favors recyclization over hydrolysis.

PubMed: 23439634
DOI: 10.1128/AAC.02247-12

Experimental method

X-RAY DIFFRACTION (1.79 Å)