A Thymine:Thymine Mismatch Enhances the Pluramycin Alkylation Site Downstream of the TBP−TATA Box Complex

Abstract

The DNA groove interactions of the pluramycins determine the base-pair specificity to the 5‘-side of the covalently modified guanine. The DNA reactivity of these drugs at defined sites can be further increased by structural and dynamic DNA distortion induced by TATA binding protein (TBP) binding to the TATA box. This enhanced drug reactivity has led to the proposal that protein-induced DNA conformational dynamics might be responsible for the more selective biological consequences of the pluramycins. To identify the structural and/or dynamic determinants that account for the enhanced drug reactivity, DNA heteroduplexes that contain base mismatches were examined for enhanced alkylation by altromycin B. The results demonstrate that base mismatches located at the 5‘-side of the target guanine enhance drug reactivity. An analysis of the structural and dynamic properties of the base mismatches demonstrates that the pluramycin reactivities are not only determined by dynamic conformation of the base mismatch, whi...