Binding inhibitors of the bacterial sliding clamp by design

Wijffels, Gene, Johnson, Wynona M., Oakley, Aaron J., Turner, Kathleen, Epa, V. Chandana, Briscoe, Susan J., Polley, Mitchell, Liepa, Andris J., Hofmann, Albert, Buchardt, Jens, Christensen, Caspar, Prosselkov, Pavel, Dalrymple, Brian P., Alewood, Paul F., Jennings, Philip A., Dixon, Nicholas E. and Winkler, David A. (2011) Binding inhibitors of the bacterial sliding clamp by design. Journal of Medicinal Chemistry, 54 13: 4831-4838. doi:10.1021/jm2004333


Author Wijffels, Gene
Johnson, Wynona M.
Oakley, Aaron J.
Turner, Kathleen
Epa, V. Chandana
Briscoe, Susan J.
Polley, Mitchell
Liepa, Andris J.
Hofmann, Albert
Buchardt, Jens
Christensen, Caspar
Prosselkov, Pavel
Dalrymple, Brian P.
Alewood, Paul F.
Jennings, Philip A.
Dixon, Nicholas E.
Winkler, David A.
Title Binding inhibitors of the bacterial sliding clamp by design
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0022-2623
1520-4804
Publication date 2011-07
Sub-type Article (original research)
DOI 10.1021/jm2004333
Volume 54
Issue 13
Start page 4831
End page 4838
Total pages 8
Place of publication Washington, DC, U.S.A.
Publisher American Chemical Society
Collection year 2012
Language eng
Formatted abstract
The bacterial replisome is a target for the development of new antibiotics to combat drug resistant strains. The β2 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 β2 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–β2 interaction at low micromolar concentrations. We report the crystal structure of the complex containing one of these inhibitors, a biphenyl oxime, bound to β2, as a starting point for further inhibitor design.
Keyword DNA-polymerase-III
Escherichia-coli
beta-Subunit
delta-Subunit
Replication
Protein
Holoenzyme
Processivity
Mechanism
β-Subunit
δ-Subunit
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
Institute for Molecular Bioscience - Publications
 
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Citation counts: TR Web of Science Citation Count  Cited 13 times in Thomson Reuters Web of Science Article | Citations
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