ArticleProtein science : a publication of the Protein Society2016
The structure of a doripenem-bound OXA-51 class D β-lactamase variant with enhanced carbapenemase activity.
Article in Protein science : a publication of the Protein Society, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers, 1 of them a synthesis that pooled it.
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Who cites it
23 citing papers in PubMed, 1 synthesis or guideline pooled it, 38 citations in OpenAlex.
- Drug-resistantClinical microbiology reviews · 2025Pooled it
- Structural insights into the activity of carbapenemases: understanding the mechanism of action of current inhibitors and informing the design of new carbapenem adjuvants.RSC medicinal chemistry · 2025Review
- Structural comparison of substrate-binding pockets of serine β-lactamases in classes A, C, and D.Journal of enzyme inhibition and medicinal chemistry · 2025Review
- Diversity in the Common Fold: Structural Insights into Class D β-Lactamases from Gram-Negative Pathogens.Pathogens (Basel, Switzerland) · 2025Article
- Structural and Dynamic Features of Acinetobacter baumannii OXA-66 β-Lactamase Explain Its Stability and Evolution of Novel Variants.Journal of molecular biology · 2024Article
- Review
- Analysis of Antimicrobial Resistance Genes (ARGs) in Enterobacterales andAntibiotics (Basel, Switzerland) · 2023Article
- Meropenem in combination with baicalein exhibits synergism against extensively drug resistant and pan-drug-resistant Acinetobacter baumannii clinical isolates in vitro.Pathogens and disease · 2023Article
- Whole-Genome Sequencing of ST2Antibiotics (Basel, Switzerland) · 2022Article
- Article
- Specific Amino Acid Substitutions in OXA-51-TypeInternational journal of molecular sciences · 2022Article
- OXA-66 structure and oligomerisation of OXAAccess microbiology · 2022Article
- Analysis of β-lactone formation by clinically observed carbapenemases informs on a novel antibiotic resistance mechanism.The Journal of biological chemistry · 2020Article
- Structural analysis of avibactam-mediated activation of the bla and mec divergons in methicillin-resistantThe Journal of biological chemistry · 2020Article
- Carbapenemases: TransformingBiomolecules · 2020Review
- Structural Analysis of The OXA-48 Carbapenemase Bound to A "Poor" Carbapenem Substrate, Doripenem.Antibiotics (Basel, Switzerland) · 2019Article
- β-Lactamases and β-Lactamase Inhibitors in the 21st Century.Journal of molecular biology · 2019Review
- Genetic and Biochemical Characterization of OXA-519, a Novel OXA-48-Like β-Lactamase.Antimicrobial agents and chemotherapy · 2018Article
- Network Analysis of Protein Adaptation: Modeling the Functional Impact of Multiple Mutations.Molecular biology and evolution · 2018Article
- A New Mechanism for β-Lactamases: Class D Enzymes Degrade 1β-Methyl Carbapenems through Lactone Formation.Angewandte Chemie (International ed. in English) · 2018Article
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
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.
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