4QU3: Ges-2 Ertapenem Acyl-enzyme Complex

Carbapenems are the last resort antibiotics for treatment of life-threatening infections. The GES beta-lactamases are important contributors to carbapenem resistance in clinical bacterial pathogens. A single amino acid difference at position 170 of the GES-1, GES-2, and GES-5 enzymes is responsible for the expansion of their substrate profile to include carbapenem antibiotics. This highlights the increasing need to understand the mechanisms by which the GES beta-lactamases function to aid in development of novel therapeutics. We demonstrate that the catalytic efficiency of the enzymes with carbapenems meropenem, ertapenem, and doripenem progressively increases (100-fold) from GES-1 to -5, mainly due to an increase in the rate of acylation. The data reveal that while acylation is rate limiting for GES-1 and GES-2 for all three carbapenems, acylation and deacylation are indistinguishable for GES-5. The ertapenem-GES-2 crystal structure shows that only the core structure of the antibiotic interacts with the active site of the GES-2 beta-lactamase. The identical core structures of ertapenem, doripenem, and meropenem are likely responsible for the observed similarities in the kinetics with these carbapenems. The lack of a methyl group in the core structure of imipenem may provide a structural rationale for the increase in turnover of this carbapenem by the GES beta-lactamases. Our data also show that in GES-2 an extensive hydrogen-bonding network between the acyl-enzyme complex and the active site water attenuates activation of this water molecule, which results in poor deacylation by this enzyme.
PDB ID: 4QU3Download
MMDB ID: 125784
PDB Deposition Date: 2014/7/10
Updated in MMDB: 2015/02
Experimental Method:
x-ray diffraction
Resolution: 1.4  Å
Source Organism:
Similar Structures:
Biological Unit for 4QU3: monomeric; determined by author and by software (PISA)
Molecular Components in 4QU3
Label Count Molecule
Protein (1 molecule)
Beta-lactamase Ges-2
Molecule annotation
Chemicals (5 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB