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| {{STRUCTURE_2aio| PDB=2aio | SCENE= }} | | {{STRUCTURE_2aio| PDB=2aio | SCENE= }} |
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| '''Metallo beta lactamase L1 from Stenotrophomonas maltophilia complexed with hydrolyzed moxalactam'''
| | ===Metallo beta lactamase L1 from Stenotrophomonas maltophilia complexed with hydrolyzed moxalactam=== |
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| ==Overview==
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| Metallo-beta-lactamases are zinc-dependent enzymes responsible for resistance to beta-lactam antibiotics in a variety of host bacteria, usually Gram-negative species that act as opportunist pathogens. They hydrolyze all classes of beta-lactam antibiotics, including carbapenems, and escape the action of available beta-lactamase inhibitors. Efforts to develop effective inhibitors have been hampered by the lack of structural information regarding how these enzymes recognize and turn over beta-lactam substrates. We report here the crystal structure of the Stenotrophomonas maltophilia L1 enzyme in complex with the hydrolysis product of the 7alpha-methoxyoxacephem, moxalactam. The on-enzyme complex is a 3'-exo-methylene species generated by elimination of the 1-methyltetrazolyl-5-thiolate anion from the 3'-methyl group. Moxalactam binding to L1 involves direct interaction of the two active site zinc ions with the beta-lactam amide and C4 carboxylate, groups that are common to all beta-lactam substrates. The 7beta-[(4-hydroxyphenyl)malonyl]-amino substituent makes limited hydrophobic and hydrogen bonding contacts with the active site groove. The mode of binding provides strong evidence that a water molecule situated between the two metal ions is the most likely nucleophile in the hydrolytic reaction. These data suggest a reaction mechanism for metallo-beta-lactamases in which both metal ions contribute to catalysis by activating the bridging water/hydroxide nucleophile, polarizing the substrate amide bond for attack and stabilizing anionic nitrogen intermediates. The structure illustrates how a binuclear zinc site confers upon metallo-beta-lactamases the ability both to recognize and efficiently hydrolyze a wide variety of beta-lactam substrates.
| | The line below this paragraph, {{ABSTRACT_PUBMED_16218639}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 16218639 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_16218639}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Metallo-beta-lactamase]] | | [[Category: Metallo-beta-lactamase]] |
| [[Category: Zinc]] | | [[Category: Zinc]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 19:05:55 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 22:36:28 2008'' |