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| - | [[Image:2aio.gif|left|200px]] | + | {{Seed}} |
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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'' |
Revision as of 19:36, 28 July 2008
Template:STRUCTURE 2aio
Metallo beta lactamase L1 from Stenotrophomonas maltophilia complexed with hydrolyzed moxalactam
Template:ABSTRACT PUBMED 16218639
About this Structure
2AIO is a Single protein structure of sequence from Stenotrophomonas maltophilia. Full crystallographic information is available from OCA.
Reference
Antibiotic recognition by binuclear metallo-beta-lactamases revealed by X-ray crystallography., Spencer J, Read J, Sessions RB, Howell S, Blackburn GM, Gamblin SJ, J Am Chem Soc. 2005 Oct 19;127(41):14439-44. PMID:16218639
Page seeded by OCA on Mon Jul 28 22:36:28 2008
