Structural insights into the design of inhibitors for the L1 metallo-beta-lactamase from Stenotrophomonas maltophilia |
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Authors: | Nauton L Kahn R Garau G Hernandez J F Dideberg O |
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Institution: | 1 Institut de Biologie Structurale Jean-Pierre Ebel (UMR 5075;CNRS;CEA;UJF), 41, rue Jules Horowitz, F-38027 Grenoble Cedex 1, France 2 Institut des Biomolécules Max Mousseron, CNRS, UMR 5247, Universités Montpellier 1 et 2, Faculté de Pharmacie, 15, Avenue Charles Flahault, F-34093 Montpellier Cedex 5, France |
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Abstract: | One mechanism by which bacteria can escape the action of β-lactam antibiotics is the production of metallo-β-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-β-lactamases, one of the main steps in structure-based drug design. |
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Keywords: | MBL metallo-β-lactamase PDB Protein Data Bank rmsd root-mean-square deviation EXAFS extended X-ray absorption fine structure D-cap d-proline" target="_blank">1-(2S)-3-mercapto-2-methyl-propionyl-d-proline MP2 l-cysteinyl glycine" target="_blank">N-[(benzyloxy) carbonyl]-l-cysteinyl glycine |
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