1L2S

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

Summary for 1L2S

• Entry DOI: 10.2210/pdb1l2s/pdb
• Descriptor: beta-lactamase, 3-[(4-CHLOROANILINO)SULFONYL]THIOPHENE-2-CARBOXYLIC ACID (3 entities in total)
• Functional Keywords: beta-lactamase-inhibitor complex, cephalosporinase, hydrolase
• Biological source: Escherichia coli
• Cellular location: Periplasm: P00811
• Total number of polymer chains: 2
• Total formula weight: 80129.15

Authors

Powers, R.A.,Morandi, F.,Shoichet, B.K. (deposition date: 2002-02-24, release date: 2002-07-17, Last modification date: 2023-08-16)

Primary citation

Powers, R.A.,Morandi, F.,Shoichet, B.K.
Structure-based discovery of a novel, noncovalent inhibitor of AmpC beta-lactamase.
Structure, 10:1013-1023, 2002

PubMed Abstract: 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.

PubMed: 12121656
DOI: 10.1016/S0969-2126(02)00799-2

Experimental method

X-RAY DIFFRACTION (1.94 Å)