1l2s
From Proteopedia
(New page: 200px<br /><applet load="1l2s" size="450" color="white" frame="true" align="right" spinBox="true" caption="1l2s, resolution 1.94Å" /> '''X-ray crystal struct...) |
|||
| Line 1: | Line 1: | ||
| - | [[Image:1l2s.jpg|left|200px]]<br /><applet load="1l2s" size=" | + | [[Image:1l2s.jpg|left|200px]]<br /><applet load="1l2s" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1l2s, resolution 1.94Å" /> | caption="1l2s, resolution 1.94Å" /> | ||
'''X-ray crystal structure of AmpC beta-lactamase from E. coli in complex with a DOCK-predicted non-covalent inhibitor'''<br /> | '''X-ray crystal structure of AmpC beta-lactamase from E. coli in complex with a DOCK-predicted non-covalent inhibitor'''<br /> | ||
==Overview== | ==Overview== | ||
| - | beta-lactamases are the most widespread resistance mechanisms to | + | 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== | ==About this Structure== | ||
| - | 1L2S 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:// | + | 1L2S 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== | ==Reference== | ||
| Line 15: | Line 15: | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Morandi, F.]] | [[Category: Morandi, F.]] | ||
| - | [[Category: Powers, R | + | [[Category: Powers, R A.]] |
| - | [[Category: Shoichet, B | + | [[Category: Shoichet, B K.]] |
[[Category: STC]] | [[Category: STC]] | ||
[[Category: beta-lactamase/inhibitor complex]] | [[Category: beta-lactamase/inhibitor complex]] | ||
[[Category: cephalosporinase]] | [[Category: cephalosporinase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:40:39 2008'' |
Revision as of 11:40, 21 February 2008
|
X-ray crystal structure of AmpC beta-lactamase from E. coli in complex with a DOCK-predicted non-covalent inhibitor
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.
About 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.
Reference
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
