Structural insights into the design of inhbitors for the L1 metallo-ß-lactamase from Stenotrophomonas maltophilia - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Journal of Molecular Biology Année : 2008

Structural insights into the design of inhbitors for the L1 metallo-ß-lactamase from Stenotrophomonas maltophilia

Résumé

One mechanism by which bacteria can escape the action of beta-lactam antibiotics is the production of metallo-beta-lactamases. Inhibition of these enzymes should restore the action of these widely used antibiotics. The tetrameric enzyme L1 from Stenotrophomonas maltophilia was used as a model system to determine a series of high-resolution crystal structures of apo, mono and bi-metal substituted proteins as well as protein-inhibitor complexes. Unexpectedly, although the apo structure revealed only few significant structural differences from the holo structure, some inhibitors were shown to induce amino acid side-chain rotations in the tightly packed active site. Moreover, one inhibitor employs a new binding mode in order to interact with the di-zinc center. This structural information could prove essential in the process of elucidation of the mode of interaction between a putative lead compound and metallo-beta-lactamases, one of the main steps in structure-based drug design.

Domaines

Chimie organique

Dates et versions

hal-00341669 , version 1 (25-11-2008)

Identifiants

Citer

Lionel Nauton, Richard Kahn, G. Garau, Jean-François Hernandez, Otto Dideberg. Structural insights into the design of inhbitors for the L1 metallo-ß-lactamase from Stenotrophomonas maltophilia. Journal of Molecular Biology, 2008, 1, pp.257-269. ⟨10.1016/j.jmb.2007.10.036⟩. ⟨hal-00341669⟩
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