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

Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11116-21. doi: 10.1073/pnas.0804754105. Epub 2008 Aug 4.

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray
  • DNA Polymerase III / antagonists & inhibitors*
  • DNA Polymerase III / chemistry*
  • Enzyme Inhibitors / chemistry*
  • Escherichia coli / enzymology*
  • Escherichia coli Proteins / antagonists & inhibitors*
  • Escherichia coli Proteins / chemistry*
  • Heterocyclic Compounds, 2-Ring / chemistry*
  • Protein Structure, Tertiary

Substances

  • Enzyme Inhibitors
  • Escherichia coli Proteins
  • Heterocyclic Compounds, 2-Ring
  • DNA Polymerase III
  • beta subunit, DNA polymerase III

Associated data

  • PDB/3D1E
  • PDB/3D1F
  • PDB/3DIG