title: Binding inhibitors of the bacterial sliding clamp by design.
abstract: The bacterial replisome is a target for the development of new antibiotics to combat drug resistant strains. The β(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 β(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 α-β(2) interaction at low micromolar concentrations. We report the crystal structure of the complex containing one of these inhibitors, a biphenyl oxime, bound to β(2), as a starting point for further inhibitor design.
authors: CSIRO Livestock Industries, St. Lucia, Queensland 4067, Australia. gene.wijffels@csiro.au
authors: Gene
authors: G
authors: Wijffels
authors: Wynona M
authors: WM
authors: Johnson
authors: Aaron J
authors: AJ
authors: Oakley
authors: Kathleen
authors: K
authors: Turner
authors: V Chandana
authors: VC
authors: Epa
authors: Susan J
authors: SJ
authors: Briscoe
authors: Mitchell
authors: M
authors: Polley
authors: Andris J
authors: AJ
authors: Liepa
authors: Albert
authors: A
authors: Hofmann
authors: Jens
authors: J
authors: Buchardt
authors: Caspar
authors: C
authors: Christensen
authors: Pavel
authors: P
authors: Prosselkov
authors: Brian P
authors: BP
authors: Dalrymple
authors: Paul F
authors: PF
authors: Alewood
authors: Philip A
authors: PA
authors: Jennings
authors: Nicholas E
authors: NE
authors: Dixon
authors: David A
authors: DA
authors: Winkler