7RP8

X-ray crystal structure of OXA-24/40 K84D in complex with imipenem

Summary for 7RP8

• Entry DOI: 10.2210/pdb7rp8/pdb
• Descriptor: Beta-lactamase, Imipenem, SULFATE ION, ... (4 entities in total)
• Functional Keywords: acyl-enzyme complex, carbapenemase, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Acinetobacter baumannii
• Total number of polymer chains: 1
• Total formula weight: 28346.37

Authors

Powers, R.A.,Mitchell, J.M.,June, C.M. (deposition date: 2021-08-03, release date: 2022-07-06, Last modification date: 2023-10-18)

Primary citation

Mitchell, J.M.,June, C.M.,Baggett, V.L.,Lowe, B.C.,Ruble, J.F.,Bonomo, R.A.,Leonard, D.A.,Powers, R.A.
Conformational flexibility in carbapenem hydrolysis drives substrate specificity of the class D carbapenemase OXA-24/40.
J.Biol.Chem., 298:102127-102127, 2022

PubMed Abstract: The evolution of multidrug resistance in Acinetobacter spp. increases the risk of our best antibiotics losing their efficacy. From a clinical perspective, the carbapenem-hydrolyzing class D β-lactamase subfamily present in Acinetobacter spp. is particularly concerning because of its ability to confer resistance to carbapenems. The kinetic profiles of class D β-lactamases exhibit variability in carbapenem hydrolysis, suggesting functional differences. To better understand the structure-function relationship between the carbapenem-hydrolyzing class D β-lactamase OXA-24/40 found in Acinetobacter 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 with meropenem, imipenem, and doripenem, with an increase in catalytic efficiency of up to fourfold. 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 β-lactamases.

PubMed: 35709986
DOI: 10.1016/j.jbc.2022.102127

Experimental method

X-RAY DIFFRACTION (2.28 Å)