1i2w
From Proteopedia
(New page: 200px<br /><applet load="1i2w" size="450" color="white" frame="true" align="right" spinBox="true" caption="1i2w, resolution 1.70Å" /> '''BETA-LACTAMASE FROM ...) |
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| - | [[Image:1i2w.jpg|left|200px]]<br /><applet load="1i2w" size=" | + | [[Image:1i2w.jpg|left|200px]]<br /><applet load="1i2w" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1i2w, resolution 1.70Å" /> | caption="1i2w, resolution 1.70Å" /> | ||
'''BETA-LACTAMASE FROM BACILLUS LICHENIFORMIS BS3 COMPLEXED WITH CEFOXITIN'''<br /> | '''BETA-LACTAMASE FROM BACILLUS LICHENIFORMIS BS3 COMPLEXED WITH CEFOXITIN'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The Bacillus licheniformis BS3 beta-lactamase catalyzes the hydrolysis of | + | The Bacillus licheniformis BS3 beta-lactamase catalyzes the hydrolysis of the beta-lactam ring of penicillins, cephalosporins, and related compounds. The production of beta-lactamases is the most common and thoroughly studied cause of antibiotic resistance. Although they escape the hydrolytic activity of the prototypical Staphylococcus aureus beta-lactamase, many cephems are good substrates for a large number of beta-lactamases. However, the introduction of a 7alpha-methoxy substituent, as in cefoxitin, extends their antibacterial spectrum to many cephalosporin-resistant Gram-negative bacteria. The 7alpha-methoxy group selectively reduces the hydrolytic action of many beta-lactamases without having a significant effect on the affinity for the target enzymes, the membrane penicillin-binding proteins. We report here the crystallographic structures of the BS3 enzyme and its acyl-enzyme adduct with cefoxitin at 1.7 A resolution. The comparison of the two structures reveals a covalent acyl-enzyme adduct with perturbed active site geometry, involving a different conformation of the omega-loop that bears the essential catalytic Glu166 residue. This deformation is induced by the cefoxitin side chain whose position is constrained by the presence of the alpha-methoxy group. The hydrolytic water molecule is also removed from the active site by the 7beta-carbonyl of the acyl intermediate. In light of the interactions and steric hindrances in the active site of the structure of the BS3-cefoxitin acyl-enzyme adduct, the crucial role of the conserved Asn132 residue is confirmed and a better understanding of the kinetic results emerges. |
==About this Structure== | ==About this Structure== | ||
| - | 1I2W is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Bacillus_licheniformis Bacillus licheniformis] with CFX and OUT 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:// | + | 1I2W is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Bacillus_licheniformis Bacillus licheniformis] with <scene name='pdbligand=CFX:'>CFX</scene> and <scene name='pdbligand=OUT:'>OUT</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=1I2W OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Dive, G.]] | [[Category: Dive, G.]] | ||
[[Category: Fonze, E.]] | [[Category: Fonze, E.]] | ||
| - | [[Category: Frere, J | + | [[Category: Frere, J M.]] |
[[Category: Sauvage, E.]] | [[Category: Sauvage, E.]] | ||
[[Category: Vanhove, M.]] | [[Category: Vanhove, M.]] | ||
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[[Category: serine beta-lactamase]] | [[Category: serine beta-lactamase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:07:24 2008'' |
Revision as of 11:07, 21 February 2008
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BETA-LACTAMASE FROM BACILLUS LICHENIFORMIS BS3 COMPLEXED WITH CEFOXITIN
Overview
The Bacillus licheniformis BS3 beta-lactamase catalyzes the hydrolysis of the beta-lactam ring of penicillins, cephalosporins, and related compounds. The production of beta-lactamases is the most common and thoroughly studied cause of antibiotic resistance. Although they escape the hydrolytic activity of the prototypical Staphylococcus aureus beta-lactamase, many cephems are good substrates for a large number of beta-lactamases. However, the introduction of a 7alpha-methoxy substituent, as in cefoxitin, extends their antibacterial spectrum to many cephalosporin-resistant Gram-negative bacteria. The 7alpha-methoxy group selectively reduces the hydrolytic action of many beta-lactamases without having a significant effect on the affinity for the target enzymes, the membrane penicillin-binding proteins. We report here the crystallographic structures of the BS3 enzyme and its acyl-enzyme adduct with cefoxitin at 1.7 A resolution. The comparison of the two structures reveals a covalent acyl-enzyme adduct with perturbed active site geometry, involving a different conformation of the omega-loop that bears the essential catalytic Glu166 residue. This deformation is induced by the cefoxitin side chain whose position is constrained by the presence of the alpha-methoxy group. The hydrolytic water molecule is also removed from the active site by the 7beta-carbonyl of the acyl intermediate. In light of the interactions and steric hindrances in the active site of the structure of the BS3-cefoxitin acyl-enzyme adduct, the crucial role of the conserved Asn132 residue is confirmed and a better understanding of the kinetic results emerges.
About this Structure
1I2W is a Single protein structure of sequence from Bacillus licheniformis with and as ligands. Active as Beta-lactamase, with EC number 3.5.2.6 Full crystallographic information is available from OCA.
Reference
Crystal structures of the Bacillus licheniformis BS3 class A beta-lactamase and of the acyl-enzyme adduct formed with cefoxitin., Fonze E, Vanhove M, Dive G, Sauvage E, Frere JM, Charlier P, Biochemistry. 2002 Feb 12;41(6):1877-85. PMID:11827533
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