PDBsum entry 4gnu

Hydrolase

PDB id: 4gnu

Contents

Protein chains

265 a.a.

Ligands

EPE ×2

Waters ×591

PDB id:

4gnu

Name:

Hydrolase

Title:

Crystal structure of ges-5 carbapenemase

Structure:

Beta-lactamase ges-5. Chain: a, b. Synonym: extended spectrum beta-lactamase ges-5, extended-spectrum beta-lactamase ges-5, ges-5, ges-5 extended-spectrum beta-lactamase, metallo-beta-lactamase blages-5. Engineered: yes

Source:

Pseudomonas aeruginosa. Organism_taxid: 287. Gene: blages-5. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.09Å R-factor: 0.157 R-free: 0.172

Authors:

C.A.Smith,S.B.Vakulenko

Key ref:

C.A.Smith et al. (2012). Structural basis for progression toward the carbapenemase activity in the GES family of β-lactamases. J Am Chem Soc, 134, 19512-19515. PubMed id: 23148776

Date:

17-Aug-12 Release date: 24-Jul-13

Protein chains

A0EL75  (A0EL75_PSEAI) -  beta-lactamase from Pseudomonas aeruginosa

Seq: 287 a.a.

Struc: 265 a.a.

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+)

J Am Chem Soc 134:19512-19515 (2012)

PubMed id: 23148776

Structural basis for progression toward the carbapenemase activity in the GES family of β-lactamases.

C.A.Smith, H.Frase, M.Toth, M.Kumarasiri, K.Wiafe, J.Munoz, S.Mobashery, S.B.Vakulenko.

ABSTRACT

Carbapenem antibiotics have become therapeutics of last resort for the treatment of difficult infections. The emergence of class-A β-lactamases that have the ability to inactivate carbapenems in the past few years is a disconcerting clinical development in light of the diminished options for treatment of infections. A member of the GES-type β-lactamase family, GES-1, turns over imipenem poorly, but the GES-5 β-lactamase is an avid catalyst for turnover of this antibiotic. We report herein high-resolution X-ray structures of the apo GES-5 β-lactamase and the GES-1 and GES-5 β-lactamases in complex with imipenem. The latter are the first structures of native class-A carbapenemases with a clinically used carbapenem antibiotic in the active site. The structural information is supplemented by information from molecular dynamics simulations, which collectively for the first time discloses how the second step of catalysis by these enzymes, namely, hydrolytic deacylation of the acyl-enzyme species, takes place effectively in the case of the GES-5 β-lactamase and significantly less so in GES-1. This information illuminates one evolutionary path that nature has taken in the direction of the inexorable emergence of resistance to carbapenem antibiotics.