A host-guest approach for determining drug-DNA interactions: An example using netropsin

Kristie D. Goodwin, Eric C. Long, Millie M. Georgiadis

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31 Scopus citations

Abstract

Netropsin is a well-characterized DNA minor groove binding compound that serves as a model for the study of drug-DNA interactions. Our laboratory has developed a novel host-guest approach to study drug-DNA interactions in which the host, the N-terminal fragment of Moloney murine leukemia virus reverse transcriptase (MMLV RT) is co-crystallized with a DNA oligonucleotide guest in the presence and absence of drug. We have co-crystallized netropsin with the RT fragment bound to the symmetric 16mer d(CTT AATTCGAATTAAG)2 and determined the structure of the complex at 1.85 Å. In contrast to previously reported netropsin-DNA structures, our oligonucleotide contains two AATT sites that bind netropsin with flanking 5′ and 3′ sequences that are not symmetric. The asymmetric unit of the RT fragment-DNA-netropsin crystals contains one protein molecule and one-half of the 16mer with one netropsin molecule bound. The guanidinium moiety of netropsin binds in a narrow part of the minor groove, while the amidinium is bound in the widest region within the site. We compare this structure to other Class I netropsin-DNA structures and find that the asymmetry of minor groove widths in the AATT site contributes to the orientation of netropsin within the groove while hydrogen bonding patterns vary in the different structures.

Original languageEnglish (US)
Pages (from-to)4106-4116
Number of pages11
JournalNucleic acids research
Volume33
Issue number13
DOIs
StatePublished - Oct 31 2005

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ASJC Scopus subject areas

  • Genetics

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