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Title: The 1.4 Å Crystal Structure of the Class D [beta]-Lactamase OXA-1 Complexed with Doripenem

Abstract

The clinical efficacy of carbapenem antibiotics depends on their resistance to the hydrolytic action of {beta}-lactamase enzymes. The structure of the class D {beta}-lactamase OXA-1 as an acyl complex with the carbapenem doripenem was determined to 1.4 {angstrom} resolution. Unlike most class A and class C carbapenem complexes, the acyl carbonyl oxygen in the OXA-1-doripenem complex is bound in the oxyanion hole. Interestingly, no water molecules were observed in the vicinity of the acyl linkage, providing an explanation for why carbapenems inhibit OXA-1. The side chain amine of K70 remains fully carboxylated in the acyl structure, and the resulting carbamate group forms a hydrogen bond to the alcohol of the 6{alpha}-hydroxyethyl moiety of doripenem. The carboxylate attached to the {beta}-lactam ring of doripenem is stabilized by a salt bridge to K212 and a hydrogen bond with T213, in lieu of the interaction with an arginine side chain found in most other {beta}-lactamase-{beta}-lactam complexes (e.g., R244 in the class A member TEM-1). This novel set of interactions with the carboxylate results in a major shift of the carbapenem's pyrroline ring compared to the structure of the same ring in meropenem bound to OXA-13. Additionally, bond angles of the pyrroline ring suggestmore » that after acylation, doripenem adopts the {Delta}{sup 1} tautomer. These findings provide important insights into the role that carbapenems may have in the inactivation process of class D {beta}-lactamases.« less

Authors:
; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1006058
Resource Type:
Journal Article
Journal Name:
Biochemistry-US
Additional Journal Information:
Journal Volume: 48; Journal Issue: (50) ; 12, 2009; Journal ID: ISSN 0006-2960
Country of Publication:
United States
Language:
ENGLISH
Subject:
08 HYDROGEN; 36 MATERIALS SCIENCE; ACYLATION; ALCOHOLS; AMINES; ANTIBIOTICS; ARGININE; BOND ANGLE; CARBAMATES; CARBONYLS; CHAINS; CRYSTAL STRUCTURE; ENZYMES; HYDROGEN; INACTIVATION; OXYGEN; RESOLUTION; WATER

Citation Formats

Schneider, Kyle D, Karpen, Mary E, Bonomo, Robert A, Leonard, David A, Powers, Rachel A, Grand Valley), and Case Western U.-Med). The 1.4 Å Crystal Structure of the Class D [beta]-Lactamase OXA-1 Complexed with Doripenem. United States: N. p., 2010. Web. doi:10.1021/bi901690r.
Schneider, Kyle D, Karpen, Mary E, Bonomo, Robert A, Leonard, David A, Powers, Rachel A, Grand Valley), & Case Western U.-Med). The 1.4 Å Crystal Structure of the Class D [beta]-Lactamase OXA-1 Complexed with Doripenem. United States. https://doi.org/10.1021/bi901690r
Schneider, Kyle D, Karpen, Mary E, Bonomo, Robert A, Leonard, David A, Powers, Rachel A, Grand Valley), and Case Western U.-Med). 2010. "The 1.4 Å Crystal Structure of the Class D [beta]-Lactamase OXA-1 Complexed with Doripenem". United States. https://doi.org/10.1021/bi901690r.
@article{osti_1006058,
title = {The 1.4 Å Crystal Structure of the Class D [beta]-Lactamase OXA-1 Complexed with Doripenem},
author = {Schneider, Kyle D and Karpen, Mary E and Bonomo, Robert A and Leonard, David A and Powers, Rachel A and Grand Valley) and Case Western U.-Med)},
abstractNote = {The clinical efficacy of carbapenem antibiotics depends on their resistance to the hydrolytic action of {beta}-lactamase enzymes. The structure of the class D {beta}-lactamase OXA-1 as an acyl complex with the carbapenem doripenem was determined to 1.4 {angstrom} resolution. Unlike most class A and class C carbapenem complexes, the acyl carbonyl oxygen in the OXA-1-doripenem complex is bound in the oxyanion hole. Interestingly, no water molecules were observed in the vicinity of the acyl linkage, providing an explanation for why carbapenems inhibit OXA-1. The side chain amine of K70 remains fully carboxylated in the acyl structure, and the resulting carbamate group forms a hydrogen bond to the alcohol of the 6{alpha}-hydroxyethyl moiety of doripenem. The carboxylate attached to the {beta}-lactam ring of doripenem is stabilized by a salt bridge to K212 and a hydrogen bond with T213, in lieu of the interaction with an arginine side chain found in most other {beta}-lactamase-{beta}-lactam complexes (e.g., R244 in the class A member TEM-1). This novel set of interactions with the carboxylate results in a major shift of the carbapenem's pyrroline ring compared to the structure of the same ring in meropenem bound to OXA-13. Additionally, bond angles of the pyrroline ring suggest that after acylation, doripenem adopts the {Delta}{sup 1} tautomer. These findings provide important insights into the role that carbapenems may have in the inactivation process of class D {beta}-lactamases.},
doi = {10.1021/bi901690r},
url = {https://www.osti.gov/biblio/1006058}, journal = {Biochemistry-US},
issn = {0006-2960},
number = (50) ; 12, 2009,
volume = 48,
place = {United States},
year = {Tue Jan 12 00:00:00 EST 2010},
month = {Tue Jan 12 00:00:00 EST 2010}
}