Structure of the B-DNA dodecamer with the reversed central sequenced(CGCGTTAACGCG) and its netropsin complex

Abstract

The novel B-DNA dodecamer sequence d(CGCGTTAACGCG) and its complex with the anticancer drug netropsin have been determined using single crystal X-ray diffraction methods. The DNA conformations in both structures are compared to understand drug-induced conformational changes. The dodecamers crystallize in isomorphous orthorhombic space group P212121 with cell constants a = 25.49 A, b = 40.84 A, and c = 67.02 A for the DNA itself, and a = 25.70 A, b = 40.50 A, and c = 67.00 A for the complex. X-ray intensity data were collected on a Siemens area detector, and the structures were refined to R factors of about 19%. The DNA molecule is bent 18° in the native structure and 24° in the netropsin complex. The narrow “cleft” formed by the T2A2 sequence at the center serves as the binding site for the drug and on binding expands the cleft from about 4 to 4.3 A. The drug is engaged in hydrogenbonding interactions with the adenine N3 and thymine O2 atoms in the floor of the minor groove covering the entire tetranucleotide stretch TTAA/AATT.