1a8t
From Proteopedia
(New page: 200px<br /><applet load="1a8t" size="450" color="white" frame="true" align="right" spinBox="true" caption="1a8t, resolution 2.55Å" /> '''METALLO-BETA-LACTAMA...) |
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| - | [[Image:1a8t.gif|left|200px]]<br /><applet load="1a8t" size=" | + | [[Image:1a8t.gif|left|200px]]<br /><applet load="1a8t" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1a8t, resolution 2.55Å" /> | caption="1a8t, resolution 2.55Å" /> | ||
'''METALLO-BETA-LACTAMASE IN COMPLEX WITH L-159,061'''<br /> | '''METALLO-BETA-LACTAMASE IN COMPLEX WITH L-159,061'''<br /> | ||
==Overview== | ==Overview== | ||
| - | BACKGROUND: High level resistance to carbapenem antibiotics in gram | + | BACKGROUND: High level resistance to carbapenem antibiotics in gram negative bacteria such as Bacteroides fragilis is caused, in part, by expression of a wide-spectrum metallo-beta-lactamase that hydrolyzes the drug to an inactive form. Co-administration of metallo-beta-lactamase inhibitors to resistant bacteria is expected to restore the antibacterial activity of carbapenems. RESULTS: Biphenyl tetrazoles (BPTs) are a structural class of potent competitive inhibitors of metallo-beta-lactamase identified through screening and predicted using molecular modeling of the enzyme structure. The X-ray crystal structure of the enzyme bound to the BPT L-159,061 shows that the tetrazole moiety of the inhibitor interacts directly with one of the two zinc atoms in the active site, replacing a metal-bound water molecule. Inhibition of metallo-beta-lactamase by BPTs in vitro correlates well with antibiotic sensitization of resistant B. fragilis. CONCLUSIONS: BPT inhibitors can sensitize a resistant B. fragilis clinical isolate expressing metallo-beta-lactamase to the antibiotics imipenem or penicillin G but not to rifampicin. |
==About this Structure== | ==About this Structure== | ||
| - | 1A8T is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Bacteroides_fragilis Bacteroides fragilis] with ZN and 061 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Beta-lactamase Beta-lactamase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.2.6 3.5.2.6] Full crystallographic information is available from [http:// | + | 1A8T is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Bacteroides_fragilis Bacteroides fragilis] with <scene name='pdbligand=ZN:'>ZN</scene> and <scene name='pdbligand=061:'>061</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Beta-lactamase Beta-lactamase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.2.6 3.5.2.6] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1A8T OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Beta-lactamase]] | [[Category: Beta-lactamase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Fitzgerald, P | + | [[Category: Fitzgerald, P M.D.]] |
[[Category: Grover, N.]] | [[Category: Grover, N.]] | ||
| - | [[Category: Toney, J | + | [[Category: Toney, J H.]] |
[[Category: Vanderwall, D.]] | [[Category: Vanderwall, D.]] | ||
[[Category: 061]] | [[Category: 061]] | ||
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[[Category: zinc]] | [[Category: zinc]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 11:42:13 2008'' |
Revision as of 09:42, 21 February 2008
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METALLO-BETA-LACTAMASE IN COMPLEX WITH L-159,061
Overview
BACKGROUND: High level resistance to carbapenem antibiotics in gram negative bacteria such as Bacteroides fragilis is caused, in part, by expression of a wide-spectrum metallo-beta-lactamase that hydrolyzes the drug to an inactive form. Co-administration of metallo-beta-lactamase inhibitors to resistant bacteria is expected to restore the antibacterial activity of carbapenems. RESULTS: Biphenyl tetrazoles (BPTs) are a structural class of potent competitive inhibitors of metallo-beta-lactamase identified through screening and predicted using molecular modeling of the enzyme structure. The X-ray crystal structure of the enzyme bound to the BPT L-159,061 shows that the tetrazole moiety of the inhibitor interacts directly with one of the two zinc atoms in the active site, replacing a metal-bound water molecule. Inhibition of metallo-beta-lactamase by BPTs in vitro correlates well with antibiotic sensitization of resistant B. fragilis. CONCLUSIONS: BPT inhibitors can sensitize a resistant B. fragilis clinical isolate expressing metallo-beta-lactamase to the antibiotics imipenem or penicillin G but not to rifampicin.
About this Structure
1A8T is a Single protein structure of sequence from Bacteroides fragilis with and as ligands. Active as Beta-lactamase, with EC number 3.5.2.6 Full crystallographic information is available from OCA.
Reference
Antibiotic sensitization using biphenyl tetrazoles as potent inhibitors of Bacteroides fragilis metallo-beta-lactamase., Toney JH, Fitzgerald PM, Grover-Sharma N, Olson SH, May WJ, Sundelof JG, Vanderwall DE, Cleary KA, Grant SK, Wu JK, Kozarich JW, Pompliano DL, Hammond GG, Chem Biol. 1998 Apr;5(4):185-96. PMID:9545432
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