1xgi: Difference between revisions
New page: left|200px<br /><applet load="1xgi" size="450" color="white" frame="true" align="right" spinBox="true" caption="1xgi, resolution 1.96Å" /> '''AmpC beta-lactamase ... |
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[[Image:1xgi.gif|left|200px]]<br /><applet load="1xgi" size=" | [[Image:1xgi.gif|left|200px]]<br /><applet load="1xgi" size="350" color="white" frame="true" align="right" spinBox="true" | ||
caption="1xgi, resolution 1.96Å" /> | caption="1xgi, resolution 1.96Å" /> | ||
'''AmpC beta-lactamase in complex with 3-(3-nitro-phenylsulfamoyl)-thiophene-2-carboxylic acid'''<br /> | '''AmpC beta-lactamase in complex with 3-(3-nitro-phenylsulfamoyl)-thiophene-2-carboxylic acid'''<br /> | ||
==Overview== | ==Overview== | ||
Bacterial expression of beta-lactamases is the most widespread resistance | Bacterial expression of beta-lactamases is the most widespread resistance mechanism to beta-lactam antibiotics, such as penicillins and cephalosporins. There is a pressing need for novel, non-beta-lactam inhibitors of these enzymes. One previously discovered novel inhibitor of the beta-lactamase AmpC, compound 1, has several favorable properties: it is chemically dissimilar to beta-lactams and is a noncovalent, competitive inhibitor of the enzyme. However, at 26 microM its activity is modest. Using the X-ray structure of the AmpC/1 complex as a template, 14 analogues were designed and synthesized. The most active of these, compound 10, had a K(i) of 1 microM, 26-fold better than the lead. To understand the origins of this improved activity, the structures of AmpC in complex with compound 10 and an analogue, compound 11, were determined by X-ray crystallography to 1.97 and 1.96 A, respectively. Compound 10 was active in cell culture, reversing resistance to the third generation cephalosporin ceftazidime in bacterial pathogens expressing AmpC. In contrast to beta-lactam-based inhibitors clavulanate and cefoxitin, compound 10 did not up-regulate beta-lactamase expression in cell culture but simply inhibited the enzyme expressed by the resistant bacteria. Its escape from this resistance mechanism derives from its dissimilarity to beta-lactam antibiotics. | ||
==About this Structure== | ==About this Structure== | ||
1XGI is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with NST as [http://en.wikipedia.org/wiki/ligand ligand]. 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:// | 1XGI is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with <scene name='pdbligand=NST:'>NST</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. 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=1XGI OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Bonnet, R.]] | [[Category: Bonnet, R.]] | ||
[[Category: Costi, M | [[Category: Costi, M P.]] | ||
[[Category: Morandi, F.]] | [[Category: Morandi, F.]] | ||
[[Category: Shoichet, B | [[Category: Shoichet, B K.]] | ||
[[Category: Tondi, D.]] | [[Category: Tondi, D.]] | ||
[[Category: NST]] | [[Category: NST]] | ||
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[[Category: serine hydrolase]] | [[Category: serine hydrolase]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:54:32 2008'' | ||
Revision as of 16:54, 21 February 2008
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AmpC beta-lactamase in complex with 3-(3-nitro-phenylsulfamoyl)-thiophene-2-carboxylic acid
OverviewOverview
Bacterial expression of beta-lactamases is the most widespread resistance mechanism to beta-lactam antibiotics, such as penicillins and cephalosporins. There is a pressing need for novel, non-beta-lactam inhibitors of these enzymes. One previously discovered novel inhibitor of the beta-lactamase AmpC, compound 1, has several favorable properties: it is chemically dissimilar to beta-lactams and is a noncovalent, competitive inhibitor of the enzyme. However, at 26 microM its activity is modest. Using the X-ray structure of the AmpC/1 complex as a template, 14 analogues were designed and synthesized. The most active of these, compound 10, had a K(i) of 1 microM, 26-fold better than the lead. To understand the origins of this improved activity, the structures of AmpC in complex with compound 10 and an analogue, compound 11, were determined by X-ray crystallography to 1.97 and 1.96 A, respectively. Compound 10 was active in cell culture, reversing resistance to the third generation cephalosporin ceftazidime in bacterial pathogens expressing AmpC. In contrast to beta-lactam-based inhibitors clavulanate and cefoxitin, compound 10 did not up-regulate beta-lactamase expression in cell culture but simply inhibited the enzyme expressed by the resistant bacteria. Its escape from this resistance mechanism derives from its dissimilarity to beta-lactam antibiotics.
About this StructureAbout this Structure
1XGI is a Single protein structure of sequence from Escherichia coli with as ligand. Active as Beta-lactamase, with EC number 3.5.2.6 Full crystallographic information is available from OCA.
ReferenceReference
Structure-based optimization of a non-beta-lactam lead results in inhibitors that do not up-regulate beta-lactamase expression in cell culture., Tondi D, Morandi F, Bonnet R, Costi MP, Shoichet BK, J Am Chem Soc. 2005 Apr 6;127(13):4632-9. PMID:15796528
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