1l2s: Difference between revisions

Revision as of 14:40, 21 February 2008

X-ray crystal structure of AmpC beta-lactamase from E. coli in complex with a DOCK-predicted non-covalent inhibitor

OverviewOverview

beta-lactamases are the most widespread resistance mechanisms to beta-lactam antibiotics, and there is a pressing need for novel, non-beta-lactam drugs. A database of over 200,000 compounds was docked to the active site of AmpC beta-lactamase to identify potential inhibitors. Fifty-six compounds were tested, and three had K(i) values of 650 microM or better. The best of these, 3-[(4-chloroanilino)sulfonyl]thiophene-2-carboxylic acid, was a competitive noncovalent inhibitor (K(i) = 26 microM), which also reversed resistance to beta-lactams in bacteria expressing AmpC. The structure of AmpC in complex with this compound was determined by X-ray crystallography to 1.94 A and reveals that the inhibitor interacts with key active-site residues in sites targeted in the docking calculation. Indeed, the experimentally determined conformation of the inhibitor closely resembles the prediction. The structure of the enzyme-inhibitor complex presents an opportunity to improve binding affinity in a novel series of inhibitors discovered by structure-based methods.

About this StructureAbout this Structure

1L2S 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 discovery of a novel, noncovalent inhibitor of AmpC beta-lactamase., Powers RA, Morandi F, Shoichet BK, Structure. 2002 Jul;10(7):1013-23. PMID:12121656

Page seeded by OCA on Thu Feb 21 13:40:39 2008

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OCA

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-[[Image:1l2s.jpg|left|200px]]<br /><applet load="1l2s" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:1l2s.jpg|left|200px]]<br /><applet load="1l2s" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="1l2s, resolution 1.94&Aring;" />
 '''X-ray crystal structure of AmpC beta-lactamase from E. coli in complex with a DOCK-predicted non-covalent inhibitor'''<br />
 ==Overview==
-beta-lactamases are the most widespread resistance mechanisms to, beta-lactam antibiotics, and there is a pressing need for novel, non-beta-lactam drugs. A database of over 200,000 compounds was docked to, the active site of AmpC beta-lactamase to identify potential inhibitors., Fifty-six compounds were tested, and three had K(i) values of 650 microM, or better. The best of these, 3-[(4-chloroanilino)sulfonyl]thiophene-2-carboxylic acid, was a, competitive noncovalent inhibitor (K(i) = 26 microM), which also reversed, resistance to beta-lactams in bacteria expressing AmpC. The structure of, AmpC in complex with this compound was determined by X-ray crystallography, to 1.94 A and reveals that the inhibitor interacts with key active-site, residues in sites targeted in the docking calculation. Indeed, the, experimentally determined conformation of the inhibitor closely resembles, the prediction. The structure of the enzyme-inhibitor complex presents an, opportunity to improve binding affinity in a novel series of inhibitors, discovered by structure-based methods.
+beta-lactamases are the most widespread resistance mechanisms to beta-lactam antibiotics, and there is a pressing need for novel, non-beta-lactam drugs. A database of over 200,000 compounds was docked to the active site of AmpC beta-lactamase to identify potential inhibitors. Fifty-six compounds were tested, and three had K(i) values of 650 microM or better. The best of these, 3-[(4-chloroanilino)sulfonyl]thiophene-2-carboxylic acid, was a competitive noncovalent inhibitor (K(i) = 26 microM), which also reversed resistance to beta-lactams in bacteria expressing AmpC. The structure of AmpC in complex with this compound was determined by X-ray crystallography to 1.94 A and reveals that the inhibitor interacts with key active-site residues in sites targeted in the docking calculation. Indeed, the experimentally determined conformation of the inhibitor closely resembles the prediction. The structure of the enzyme-inhibitor complex presents an opportunity to improve binding affinity in a novel series of inhibitors discovered by structure-based methods.
 ==About this Structure==
-L2S 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 STC 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://ispc.weizmann.ac.il/oca-bin/ocashort?id=1L2S OCA].
+L2S 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=STC:'>STC</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=1L2S OCA].
 ==Reference==
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 [[Category: Single protein]]
 [[Category: Morandi, F.]]
-[[Category: Powers, R.A.]]
+[[Category: Powers, R A.]]
-[[Category: Shoichet, B.K.]]
+[[Category: Shoichet, B K.]]
 [[Category: STC]]
 [[Category: beta-lactamase/inhibitor complex]]
 [[Category: cephalosporinase]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Nov 20 20:11:55 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:40:39 2008''