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CRYSTAL STRUCTURE OF OXA-405 BETA-LACTAMASECRYSTAL STRUCTURE OF OXA-405 BETA-LACTAMASE
Structural highlights
FunctionPublication Abstract from PubMedOXA-48-producing Enterobacterales have now widely disseminated globally. A sign of their extensive spread is the identification of an increasing number of OXA-48 variants. Among them, three are particularly interesting, OXA-163, OXA-247 and OXA-405, since they have lost carbapenem activities and gained expanded-spectrum cephalosporin hydrolytic activity subsequent to a four amino-acid (AA) deletion in the beta5-beta6 loop. We investigated the mechanisms responsible for substrate specificity of OXA-405. Kinetic parameters confirmed that OXA-405 has a hydrolytic profile compatible with an ESBL (hydrolysis of expanded spectrum cephalosporins and susceptibility to class A inhibitors). Molecular modeling techniques and 3D structure determination show that the overall dimeric structure of OXA-405 is very similar to that of OXA-48, except for the beta5-beta6 loop, which is shorter for OXA-405, suggesting that the length of the beta5-beta6 loop is critical for substrate specificity. Covalent docking with selected substrates and molecular dynamics simulations evidenced the structural changes induced by substrate binding, as well as the distribution of water molecules in the active site and their role in substrate hydrolysis. All this data may represent the structural basis for the design of new and efficient class D inhibitors. Biochemical and Structural Characterization of OXA-405, an OXA-48 Variant with Extended-Spectrum beta-Lactamase Activity.,Oueslati S, Retailleau P, Marchini L, Dortet L, Bonnin RA, Iorga BI, Naas T Microorganisms. 2019 Dec 21;8(1). pii: microorganisms8010024. doi:, 10.3390/microorganisms8010024. PMID:31877796[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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