Structures of the Class D Carbapenemase OXA-24 from Acinetobacter baumannii in Complex with Doripenem
Abstract
The emergence of class D {beta}-lactamases with carbapenemase activity presents an enormous challenge to health practitioners, particularly with regard to the treatment of infections caused by Gram-negative pathogens such as Acinetobacter baumannii. Unfortunately, class D {beta}-lactamases with carbapenemase activity are resistant to {beta}-lactamase inhibitors. To better understand the details of the how these enzymes bind and hydrolyze carbapenems, we have determined the structures of two deacylation-deficient variants (K84D and V130D) of the class D carbapenemase OXA-24 with doripenem bound as a covalent acyl-enzyme intermediate. Doripenem adopts essentially the same configuration in both OXA-24 variant structures, but varies significantly when compared to the non-carbapenemase class D member OXA-1/doripenem complex. The alcohol of the 6a hydroxyethyl moiety is directed away from the general base carboxy-K84, with implications for activation of the deacylating water. The tunnel formed by the Y112/M223 bridge in the apo form of OXA-24 is largely unchanged by the binding of doripenem. The presence of this bridge, however, causes the distal pyrrolidine/sulfonamide group to bind in a drastically different conformation compared to doripenem bound to OXA-1. The resulting difference in the position of the side-chain bridge sulfur of doripenem is consistent with the hypothesis that the tautomeric state of themore »
- Authors:
-
- Case Western
- Publication Date:
- Research Org.:
- Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- NIHOTHER U.S. GOVERNMENT
- OSTI Identifier:
- 1031369
- Resource Type:
- Journal Article
- Journal Name:
- J. Mol. Biol.
- Additional Journal Information:
- Journal Volume: 406; Journal Issue: (4) ; 03, 2011; Journal ID: ISSN 0022-2836
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; ALCOHOLS; CONFIGURATION; DESIGN; ENZYMES; HYDROLYSIS; HYPOTHESIS; PATHOGENS; SULFUR; WATER
Citation Formats
Schneider, Kyle D, Ortega, Caleb J, Renck, Nicholas A, Bonomo, Robert A, Powers, Rachel A, Leonard, David A, and Grand Valley). Structures of the Class D Carbapenemase OXA-24 from Acinetobacter baumannii in Complex with Doripenem. United States: N. p., 2012.
Web. doi:10.1016/j.jmb.2010.12.042.
Schneider, Kyle D, Ortega, Caleb J, Renck, Nicholas A, Bonomo, Robert A, Powers, Rachel A, Leonard, David A, & Grand Valley). Structures of the Class D Carbapenemase OXA-24 from Acinetobacter baumannii in Complex with Doripenem. United States. https://doi.org/10.1016/j.jmb.2010.12.042
Schneider, Kyle D, Ortega, Caleb J, Renck, Nicholas A, Bonomo, Robert A, Powers, Rachel A, Leonard, David A, and Grand Valley). 2012.
"Structures of the Class D Carbapenemase OXA-24 from Acinetobacter baumannii in Complex with Doripenem". United States. https://doi.org/10.1016/j.jmb.2010.12.042.
@article{osti_1031369,
title = {Structures of the Class D Carbapenemase OXA-24 from Acinetobacter baumannii in Complex with Doripenem},
author = {Schneider, Kyle D and Ortega, Caleb J and Renck, Nicholas A and Bonomo, Robert A and Powers, Rachel A and Leonard, David A and Grand Valley)},
abstractNote = {The emergence of class D {beta}-lactamases with carbapenemase activity presents an enormous challenge to health practitioners, particularly with regard to the treatment of infections caused by Gram-negative pathogens such as Acinetobacter baumannii. Unfortunately, class D {beta}-lactamases with carbapenemase activity are resistant to {beta}-lactamase inhibitors. To better understand the details of the how these enzymes bind and hydrolyze carbapenems, we have determined the structures of two deacylation-deficient variants (K84D and V130D) of the class D carbapenemase OXA-24 with doripenem bound as a covalent acyl-enzyme intermediate. Doripenem adopts essentially the same configuration in both OXA-24 variant structures, but varies significantly when compared to the non-carbapenemase class D member OXA-1/doripenem complex. The alcohol of the 6a hydroxyethyl moiety is directed away from the general base carboxy-K84, with implications for activation of the deacylating water. The tunnel formed by the Y112/M223 bridge in the apo form of OXA-24 is largely unchanged by the binding of doripenem. The presence of this bridge, however, causes the distal pyrrolidine/sulfonamide group to bind in a drastically different conformation compared to doripenem bound to OXA-1. The resulting difference in the position of the side-chain bridge sulfur of doripenem is consistent with the hypothesis that the tautomeric state of the pyrroline ring contributes to the different carbapenem hydrolysis rates of OXA-1 and OXA-24. These findings represent a snapshot of a key step in the catalytic mechanism of an important class D enzyme, and might be useful for the design of novel inhibitors.},
doi = {10.1016/j.jmb.2010.12.042},
url = {https://www.osti.gov/biblio/1031369},
journal = {J. Mol. Biol.},
issn = {0022-2836},
number = (4) ; 03, 2011,
volume = 406,
place = {United States},
year = {Wed Feb 08 00:00:00 EST 2012},
month = {Wed Feb 08 00:00:00 EST 2012}
}