The 1.4 Å Crystal Structure of the Class D [beta]-Lactamase OXA-1 Complexed with Doripenem
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.
- Research Organization:
- Argonne National Lab. (ANL), Argonne, IL (United States)
- Sponsoring Organization:
- USDOE
- OSTI ID:
- 1006058
- Journal Information:
- Biochemistry-US, Vol. 48, Issue (50) ; 12, 2009; ISSN 0006-2960
- Country of Publication:
- United States
- Language:
- ENGLISH
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