7rp8 | pdb_00007rp8
X-ray crystal structure of OXA-24/40 K84D in complex with imipenem
Structural highlights
FunctionPublication Abstract from PubMedThe evolution of multidrug resistance (MDR) in Acinetobacter spp. increases the risk of our best antibiotics losing their efficacy. From a clinical perspective, the carbapenem-hydrolyzing class D beta-lactamase (CHDL) subfamily present in Acetinobacter spp. is particularly concerning due to its ability to confer resistance to carbapenems. The kinetic profiles of class D beta-lactamases exhibit variability in carbapenem hydrolysis, suggesting functional differences. To better understand the structure-function relationship between the CHDL OXA-24/40 found in A. baumannii and carbapenem substrates, we analyzed steady-state kinetics with the carbapenem antibiotics meropenem and ertapenem, and determined the structures of complexes of OXA-24/40 bound to imipenem, meropenem, doripenem, and ertapenem, as well as the expanded-spectrum cephalosporin cefotaxime, using X-ray crystallography. We show that OXA-24/40 exhibits a preference for ertapenem compared to meropenem, imipenem, and doripenem, with an increase in catalytic efficiency of up to four-fold. We suggest that superposition of the nine OXA-24/40 complexes will better inform future inhibitor design efforts by providing insight into the complicated and varying ways in which carbapenems are selected and bound by class D beta-lactamases. Conformational flexibility in carbapenem hydrolysis drives substrate specificity of the class D carbapenemase OXA-24/40.,Mitchell JM, June CM, Baggett VL, Lowe BC, Ruble JF, Bonomo RA, Leonard DA, Powers RA J Biol Chem. 2022 Jun 13:102127. doi: 10.1016/j.jbc.2022.102127. PMID:35709986[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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