4X53

Structure of the class D Beta-Lactamase OXA-160 V130D in Acyl-Enzyme Complex with Aztreonam

Summary for 4X53

• Entry DOI: 10.2210/pdb4x53/pdb
• Related: 4X55 4X56
• Descriptor: Class D beta-lactamase OXA-160, 2-({[(1Z)-1-(2-amino-1,3-thiazol-4-yl)-2-oxo-2-{[(2S,3S)-1-oxo-3-(sulfoamino)butan-2-yl]amino}ethylidene]amino}oxy)-2-methylpropanoic acid, BICARBONATE ION, ... (4 entities in total)
• Functional Keywords: hydrolase, carbapenemase, antibiotic
• Biological source: Acinetobacter baumannii
• Total number of polymer chains: 1
• Total formula weight: 28179.24

Authors

Clasman, J.R.,June, C.M.,Powers, R.A.,Leonard, D.A. (deposition date: 2014-12-04, release date: 2015-03-11, Last modification date: 2024-10-30)

Primary citation

Mitchell, J.M.,Clasman, J.R.,June, C.M.,Kaitany, K.C.,LaFleur, J.R.,Taracila, M.A.,Klinger, N.V.,Bonomo, R.A.,Wymore, T.,Szarecka, A.,Powers, R.A.,Leonard, D.A.
Structural Basis of Activity against Aztreonam and Extended Spectrum Cephalosporins for Two Carbapenem-Hydrolyzing Class D beta-Lactamases from Acinetobacter baumannii.
Biochemistry, 54:1976-1987, 2015

PubMed Abstract: The carbapenem-hydrolyzing class D β-lactamases OXA-23 and OXA-24/40 have emerged worldwide as causative agents for β-lactam antibiotic resistance in Acinetobacter species. Many variants of these enzymes have appeared clinically, including OXA-160 and OXA-225, which both contain a P → S substitution at homologous positions in the OXA-24/40 and OXA-23 backgrounds, respectively. We purified OXA-160 and OXA-225 and used steady-state kinetic analysis to compare the substrate profiles of these variants to their parental enzymes, OXA-24/40 and OXA-23. OXA-160 and OXA-225 possess greatly enhanced hydrolytic activities against aztreonam, ceftazidime, cefotaxime, and ceftriaxone when compared to OXA-24/40 and OXA-23. These enhanced activities are the result of much lower Km values, suggesting that the P → S substitution enhances the binding affinity of these drugs. We have determined the structures of the acylated forms of OXA-160 (with ceftazidime and aztreonam) and OXA-225 (ceftazidime). These structures show that the R1 oxyimino side-chain of these drugs occupies a space near the β5-β6 loop and the omega loop of the enzymes. The P → S substitution found in OXA-160 and OXA-225 results in a deviation of the β5-β6 loop, relieving the steric clash with the R1 side-chain carboxypropyl group of aztreonam and ceftazidime. These results reveal worrying trends in the enhancement of substrate spectrum of class D β-lactamases but may also provide a map for β-lactam improvement.

PubMed: 25710192
DOI: 10.1021/bi501547k

Experimental method

X-RAY DIFFRACTION (2.3 Å)