Open AccessStructure of a small-molecule inhibitor of a DNA polymerase sliding clamp
Author(s) -
Roxana E. Georgescu,
Olga Yurieva,
Seung-Sup Kim,
John Kuriyan,
XiangPeng Kong,
Mike O’Donnell
Publication year - 2008
Publication title -
proceedings of the national academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0804754105
Subject(s) - dna clamp , dna polymerase , polymerase , dna polymerase beta , dna polymerase ii , dna polymerase delta , biology , dna , biophysics , dna polymerase mu , dna polymerase i , biochemistry , binding site , microbiology and biotechnology , chemistry , dna repair , circular bacterial chromosome , polymerase chain reaction , gene , base excision repair , reverse transcriptase
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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