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Structure of a small-molecule inhibitor of a DNA polymerase sliding clamp.

Georgescu RE, Yurieva O, Kim SS, Kuriyan J, Kong XP, O'Donnell M
Proc Natl Acad Sci U S A 105 11116-21 (2008)
Related entries: 3d1e, 3d1g

Cited: 58 times
EuropePMC logo PMID: 18678908

Abstract

DNA polymerases attach to the DNA sliding clamp through a common overlapping binding site. We identify a small-molecule compound that binds the protein-binding site in the Escherichia coli beta-clamp and differentially affects the activity of DNA polymerases II, III, and IV. To understand the molecular basis of this discrimination, the cocrystal structure of the chemical inhibitor is solved in complex with beta and is compared with the structures of Pol II, Pol III, and Pol IV peptides bound to beta. The analysis reveals that the small molecule localizes in a region of the clamp to which the DNA polymerases attach in different ways. The results suggest that the small molecule may be useful in the future to probe polymerase function with beta, and that the beta-clamp may represent an antibiotic target.

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  2. Novel Antibiotics Targeting Bacterial Replicative DNA Polymerases. Santos JA, Lamers MH. Antibiotics (Basel) 9 E776 (2020)

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  2. Architecture and conservation of the bacterial DNA replication machinery, an underexploited drug target. Robinson A, Causer RJ, Dixon NE. Curr Drug Targets 13 352-372 (2012)
  3. Replicative DNA polymerases. Johansson E, Dixon N. Cold Spring Harb Perspect Biol 5 a012799 (2013)
  4. Rhodanine as a scaffold in drug discovery: a critical review of its biological activities and mechanisms of target modulation. Tomašić T, Peterlin Mašič L. Expert Opin Drug Discov 7 549-560 (2012)
  5. Essential biological processes of an emerging pathogen: DNA replication, transcription, and cell division in Acinetobacter spp. Robinson A, Brzoska AJ, Turner KM, Withers R, Harry EJ, Lewis PJ, Dixon NE. Microbiol Mol Biol Rev 74 273-297 (2010)
  6. Transcription of the T4 late genes. Geiduschek EP, Kassavetis GA. Virol J 7 288 (2010)
  7. Targeting DNA Replication and Repair for the Development of Novel Therapeutics against Tuberculosis. Reiche MA, Warner DF, Mizrahi V. Front Mol Biosci 4 75 (2017)
  8. A structural view of bacterial DNA replication. Oakley AJ. Protein Sci 28 990-1004 (2019)
  9. Protein-protein interactions as antibiotic targets: A medicinal chemistry perspective. Cossar PJ, Lewis PJ, McCluskey A. Med Res Rev 40 469-494 (2020)
  10. DNA Sliding Clamps as Therapeutic Targets. Altieri AS, Kelman Z. Front Mol Biosci 5 87 (2018)
  11. DNA Replication in Mycobacterium tuberculosis. Ditse Z, Lamers MH, Warner DF. Microbiol Spectr 5 (2017)
  12. Development of Protein-Protein Interaction Inhibitors for the Treatment of Infectious Diseases. Voter AF, Keck JL. Adv Protein Chem Struct Biol 111 197-222 (2018)
  13. Modulators of protein-protein interactions as antimicrobial agents. Kahan R, Worm DJ, de Castro GV, Ng S, Barnard A. RSC Chem Biol 2 387-409 (2021)
  14. The Macromolecular Machines that Duplicate the Escherichia coli Chromosome as Targets for Drug Discovery. Kaguni JM. Antibiotics (Basel) 7 E23 (2018)
  15. Protein-protein interactions in bacteria: a promising and challenging avenue towards the discovery of new antibiotics. Carro L. Beilstein J Org Chem 14 2881-2896 (2018)
  16. Blocking the Trigger: Inhibition of the Initiation of Bacterial Chromosome Replication as an Antimicrobial Strategy. Grimwade JE, Leonard AC. Antibiotics (Basel) 8 E111 (2019)
  17. Inhibition of Replication Fork Formation and Progression: Targeting the Replication Initiation and Primosomal Proteins. Radford HM, Toft CJ, Sorenson AE, Schaeffer PM. Int J Mol Sci 24 8802 (2023)

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