6HB8

Crystal structure of OXA-517 beta-lactamase

Summary for 6HB8

• Entry DOI: 10.2210/pdb6hb8/pdb
• Descriptor: Beta-lactamase, SULFATE ION, 2-ETHOXYETHANOL, ... (7 entities in total)
• Functional Keywords: beta-lactamase, hydrolase
• Biological source: Klebsiella pneumoniae
• Total number of polymer chains: 4
• Total formula weight: 120820.87

Authors

Raczynska, J.E.,Dabos, L.,Zavala, A.,Retailleau, P.,Iorga, B.,Jaskolski, M.,Naas, T. (deposition date: 2018-08-09, release date: 2019-08-28, Last modification date: 2026-09-09)

Primary citation

Dabos, L.,Raczynska, J.E.,Bogaerts, P.,Zavala, A.,Girlich, D.,Bonnin, R.A.,Dortet, L.,Peyrat, A.,Retailleau, P.,Iorga, B.I.,Jaskolski, M.,Glupczynski, Y.,Naas, T.
Structural and Biochemical Features of OXA-517: a Carbapenem and Expanded-Spectrum Cephalosporin Hydrolyzing OXA-48 Variant.
Antimicrob.Agents Chemother., 67:e0109522-e0109522, 2023

PubMed Abstract: OXA-48-producing Enterobacterales have now widely disseminated throughout the world. Several variants have now been reported, differing by just a few amino-acid substitutions or deletions, mostly in the region of the loop β5-β6. As OXA-48 hydrolyzes carbapenems but lacks significant expanded-spectrum cephalosporin (ESC) hydrolytic activity, ESCs were suggested as a therapeutic option. Here, we have characterized OXA-517, a natural variant of OXA-48- with an Arg214Lys substitution and a deletion of Ile215 and Glu216 in the β5-β6 loop, capable of hydrolyzing at the same time ESC and carbapenems. MICs values of E. coli expressing gene revealed reduced susceptibility to carbapenems (similarly to OXA-48) and resistance to ESCs. Steady-state kinetic parameters revealed high catalytic efficiencies for ESCs and carbapenems. The gene was located on a ca. 31-kb plasmid identical to the prototypical IncL -carrying plasmid except for an IS-mediated deletion of 30.7-kb in the operon. The crystal structure of OXA-517, determined to 1.86 Å resolution, revealed an expanded active site compared to that of OXA-48, which allows for accommodation of the bulky ceftazidime substrate. Our work illustrates the remarkable propensity of OXA-48-like carbapenemases to evolve through mutation/deletion in the β5-β6 loop to extend its hydrolysis profile to encompass most β-lactam substrates.

PubMed: 36648230
DOI: 10.1128/aac.01095-22

Experimental method

X-RAY DIFFRACTION (1.86 Å)