3qsb

Publication Abstract from PubMed

The bacterial replisome is a target for development of new antibiotics to combat drug resistant strains. The beta₂ sliding clamp is an essential component of the replicative machinery, providing a platform for recruitment and function of other replisomal components and ensuring polymerase processivity during DNA replication and repair. A single binding region of the clamp is utilized by its binding partners, which all contain conserved binding motifs. The C-terminal Leu and Phe residues of these motifs are integral to the binding interaction. We acquired three dimensional structural information on the binding site in beta₂ by study of binding of modified peptides. Development of a three dimensional pharmacophore based on the C-terminal dipeptide of the motif enabled identification of compounds that on further development inhibited alpha-beta₂ interaction at low muM concentrations. We report the crystal structure of the complex containing one of these inhibitors, a biphenyl oxime, bound to beta₂, as a starting point for further inhibitor design.

Binding Inhibitors of the Bacterial Sliding Clamp by Design.,Wijffels G, Johnson WM, Oakley AJ, Turner K, Epa VC, Briscoe SJ, Polley M, Liepa AJ, Hofmann A, Buchardt J, Christensen C, Prosselkov P, Dalrymple BP, Alewood PF, Jennings PA, Dixon NE, Winkler DA J Med Chem. 2011 May 23. PMID:21604761^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.