4hef

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Structure of avibactam bound to Pseudomonas aeruginosa AmpCStructure of avibactam bound to Pseudomonas aeruginosa AmpC

Structural highlights

4hef is a 1 chain structure with sequence from Pseae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:,
Gene:ampC, PA4110 (PSEAE)
Activity:Beta-lactamase, with EC number 3.5.2.6
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Publication Abstract from PubMed

Although beta-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 beta-lactamase enzymes that are not affected by currently marketed beta-lactam/beta-lactamase inhibitor combinations. Avibactam is a novel, covalent, non-beta-lactam beta-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 beta-lactamases. Here we describe the structure of two clinically important beta-lactamase enzymes bound to avibactam, the class A CTX-M-15 extended-spectrum beta-lactamase and class C Pseudomonas aeruginosa AmpC beta-lactamase, which together provide insight into the binding modes for the respective enzyme classes. The structure reveals a similar binding mode in both enzymes and thus provides 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 structure provides 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.

Structural Insight into Potent Broad-spectrum Inhibition with Reversible Recyclization Mechanism: Avibactam in Complex with CTX-M-15 and Pseudomonas aeruginosa AmpC beta-lactamases.,Lahiri SD, Mangani S, Durand-Reville T, Benvenuti M, De Luca F, Sanyal G, Docquier JD Antimicrob Agents Chemother. 2013 Feb 25. PMID:23439634[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. Lahiri SD, Mangani S, Durand-Reville T, Benvenuti M, De Luca F, Sanyal G, Docquier JD. 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. 2013 Feb 25. PMID:23439634 doi:10.1128/AAC.02247-12

4hef, resolution 1.86Å

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