1ZKJ: Structural Basis For The Extended Substrate Spectrum Of Cmy- 10, A Plasmid-encoded Class C Beta-lactamase

Citation:
Abstract
The emergence and dissemination of extended-spectrum (ES) beta-lactamases induce therapeutic failure and a lack of eradication of clinical isolates even by third-generation beta-lactam antibiotics like ceftazidime. CMY-10 is a plasmid-encoded class C beta-lactamase with a wide spectrum of substrates. Unlike the well-studied class C ES beta-lactamase from Enterobacter cloacae GC1, the Omega-loop does not affect the active site conformation and the catalytic activity of CMY-10. Instead, a three-amino-acid deletion in the R2-loop appears to be responsible for the ES activity of CMY-10. According to the crystal structure solved at 1.55 A resolution, the deletion significantly widens the R2 active site, which accommodates the R2 side-chains of beta-lactam antibiotics. This observation led us to demonstrate the hydrolysing activity of CMY-10 towards imipenem with a long R2 substituent. The forced mutational analyses of P99 beta-lactamase reveal that the introduction of deletion mutations into the R2-loop is able to extend the substrate spectrum of class C non-ES beta-lactamases, which is compatible with the isolation of natural class C ES enzymes harbouring deletion mutations in the R2-loop. Consequently, the opening of the R2 active site by the deletion of some residues in the R2-loop can be considered as an operative molecular strategy of class C beta-lactamases to extend their substrate spectrum.
PDB ID: 1ZKJDownload
MMDB ID: 38497
PDB Deposition Date: 2005/5/3
Updated in MMDB: 2007/10
Experimental Method:
x-ray diffraction
Resolution: 1.55  Å
Source Organism:
Similar Structures:
Biological Unit for 1ZKJ: monomeric; determined by author and by software (PISA)
Molecular Components in 1ZKJ
Label Count Molecule
Protein (1 molecule)
1
Extended-spectrum Beta-lactamase
Molecule annotation
Chemicals (12 molecules)
1
8
2
4
* Click molecule labels to explore molecular sequence information.

Citing MMDB
.