DNA polymerase template interactions probed by degenerate isosteric nucleobase analogs

Natasha Paul, Vishal C. Nashine, Geoffrey Hoops, Peiming Zhang, Jie Zhou, Donald E. Bergstrom, V. Jo Davisson

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

The development of novel artificial nucleobases and detailed X-ray crystal structures for primer/template/DNA polymerase complexes provide opportunities to assess DNA-protein interactions that dictate specificity. Recent results have shown that base pair shape recognition in the context of DNA polymerase must be considered a significant component. The isosteric azole carboxamide nucleobases (compounds 1-5; Figure 1) differ only in the number and placement of nitrogen atoms within a common shape and therefore present unique electronic distributions that are shown to dictate the selectivity of template-directed nucleotide incorporation by DNA polymerases. The results demonstrate how nucleoside triphosphate substrate selection by DNA polymerase is a complex phenomenon involving electrostatic interactions in addition to hydrogen bonding and shape recognition. These azole nucleobase analogs offer unique molecular tools for probing nonbonded interactions dictating substrate selection and fidelity of DNA polymerases.

Original languageEnglish (US)
Pages (from-to)815-825
Number of pages11
JournalChemistry and Biology
Volume10
Issue number9
DOIs
StatePublished - Sep 1 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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