PDBsum entry 4hef

Hydrolase/hydrolase inhibitor

PDB id: 4hef

Contents

Protein chain

360 a.a.

Ligands

GOL ×2

NXL

Waters ×341

PDB id:

4hef

Name:

Hydrolase/hydrolase inhibitor

Title:

Structure of avibactam bound to pseudomonas aeruginosa ampc

Structure:

Beta-lactamase. Chain: a. Fragment: unp residues 29-388. Synonym: cephalosporinase. Engineered: yes

Source:

Pseudomonas aeruginosa. Organism_taxid: 208964. Strain: atcc 15692 / pao1 / 1c / prs 101 / lmg 12228. Gene: ampc, pa4110. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.86Å R-factor: 0.176 R-free: 0.202

Authors:

S.D.Lahiri

Key ref:

S.D.Lahiri et al. (2013). Structural insight into potent broad-spectrum inhibition with reversible recyclization mechanism: avibactam in complex with CTX-M-15 and Pseudomonas aeruginosa AmpC β-lactamases. Antimicrob Agents Chemother, 57, 2496-2505. PubMed id: 23439634 DOI: 10.1128/AAC.02247-12

Date:

03-Oct-12 Release date: 05-Jun-13

Protein chain

P24735  (AMPC_PSEAE) -  Beta-lactamase from Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1)

Seq: 397 a.a.

Struc: 360 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.3.5.2.6 - beta-lactamase.
• Pathway: Penicillin Biosynthesis and Metabolism
• Reaction: a beta-lactam + H2O = a substituted beta-amino acid
• Cofactor: Zn(2+)

DOI no: 10.1128/AAC.02247-12

Antimicrob Agents Chemother 57:2496-2505 (2013)

PubMed id: 23439634

Structural insight into potent broad-spectrum inhibition with reversible recyclization mechanism: avibactam in complex with CTX-M-15 and Pseudomonas aeruginosa AmpC β-lactamases.

S.D.Lahiri, S.Mangani, T.Durand-Reville, M.Benvenuti, F.De Luca, G.Sanyal, J.D.Docquier.

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.