4n99

E. coli sliding clamp in complex with 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-7-carboxylic acid

spinqualitylabelsall models 4n99, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4n99 is a 2 chain structure with sequence from Escherichia coli K-12. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.3Å Ligands: 2J1, CA, PEG, PG4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function DPO3B_ECOLI DNA polymerase III is a complex, multichain enzyme responsible for most of the replicative synthesis in bacteria. This DNA polymerase also exhibits 3' to 5' exonuclease activity. The beta chain is required for initiation of replication once it is clamped onto DNA, it slides freely (bidirectional and ATP-independent) along duplex DNA. Publication Abstract from PubMed The bacterial sliding clamp (SC), also known as the DNA polymerase III beta subunit, is an emerging antibacterial target that plays a central role in DNA replication, serving as a protein-protein interaction hub with a common binding pocket to recognize linear motifs in the partner proteins. Here, fragment-based screening using X-ray crystallography produced four hits bound in the linear-motif-binding pocket of the Escherichia coli SC. Compounds structurally related to the hits were identified that inhibited the E. coli SC and SC-mediated DNA replication in vitro. A tetrahydrocarbazole derivative emerged as a promising lead whose methyl and ethyl ester prodrug forms showed minimum inhibitory concentrations in the range of 21-43 mug/mL against representative Gram-negative and Gram-positive bacteria species. The work demonstrates the utility of a fragment-based approach for identifying bacterial sliding clamp inhibitors as lead compounds with broad-spectrum antibacterial activity. Discovery of lead compounds targeting the bacterial sliding clamp using a fragment-based approach.,Yin Z, Whittell LR, Wang Y, Jergic S, Liu M, Harry EJ, Dixon NE, Beck JL, Kelso MJ, Oakley AJ J Med Chem. 2014 Mar 27;57(6):2799-806. doi: 10.1021/jm500122r. Epub 2014 Mar 18. PMID:24592885 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also DNA polymerase 3D structures

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