The structure of a doripenem-bound OXA-51 class D β-lactamase variant with enhanced carbapenemase activity

Cynthia M. June, Taylor J. Muckenthaler, Emma C. Schroder, Zachary L. Klamer, Zdzislaw Wawrzak, Rachel A. Powers, Agnieszka Szarecka, David A. Leonard*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    18 Scopus citations


    OXA-51 is a class D β-lactamase that is thought to be the native carbapenemase of Acinetobacter baumannii. Many variants of OXA-51 containing active site substitutions have been identified from A. baumannii isolates, and some of these substitutions increase hydrolytic activity toward carbapenem antibiotics. We have determined the high-resolution structures of apo OXA-51 and OXA-51 with one such substitution (I129L) with the carbapenem doripenem trapped in the active site as an acyl-intermediate. The structure shows that acyl-doripenem adopts an orientation very similar to carbapenem ligands observed in the active site of OXA-24/40 (doripenem) and OXA-23 (meropenem). In the OXA-51 variant/doripenem complex, the indole ring of W222 is oriented away from the doripenem binding site, thereby eliminating a clash that is predicted to occur in wildtype OXA-51. Similarly, in the OXA-51 variant complex, L129 adopts a different rotamer compared to I129 in wildtype OXA-51. This alternative position moves its side chain away from the hydroxyethyl moiety of doripenem and relieves another potential clash between the enzyme and carbapenem substrates. Molecular dynamics simulations of OXA-51 and OXA-51 I129L demonstrate that compared to isoleucine, a leucine at this position greatly favors a rotamer that accommodates the ligand. These results provide a molecular justification for how this substitution generates enhanced binding affinity for carbapenems, and therefore helps explain the prevalence of this substitution in clinical OXA-51 variants.

    Original languageEnglish (US)
    Pages (from-to)2152-2163
    Number of pages12
    JournalProtein Science
    Issue number12
    StatePublished - Dec 1 2016


    • antibiotic resistance
    • carbapenem
    • crystal structure
    • β-lactamase

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology


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