National Center for
3QSB: Structure of E. coli polIIIbeta with (Z)-5-(1-((4'-Fluorobiphenyl-4-yl)methoxyimino)butyl)-2,2-dimethyl-4,6-dioxocyclohexanecarbonitrile
J. Med. Chem. (2011) 54 p.4831-4838
The bacterial replisome is a target for the development of new antibiotics to combat drug resistant strains. The beta(2) 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 beta(2) by a study of the 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-beta(2) interaction at low micromolar concentrations. We report the crystal structure of the complex containing one of these inhibitors, a biphenyl oxime, bound to beta(2), as a starting point for further inhibitor design.