Structure of a bis-Intercalated DNA Complex Solved by MAD Phasing. Xiuqi Shui¹, Mary E. Peek², Qi Gao³, Craig Ogata⁴, Gary Hu¹, Bernard P. Roques⁵, Christiane Garbay-Jaureguiberry5, and Loren Dean Williams¹; ¹School of Chemistry & Biochemistry, Georgia Institute of Technology, GA 30332-0400, ²Massey Cancer Center, Medical College of Virginia, Richmond, VA 23298-0230, ³Bristol-Myers Squibb, Wallingford, CT 06492-7660, ⁴NSLS, Brookhaven National Laboratory, Upton, NY 11973, ⁵Universite Rene Descartes (Paris V), UFR des Sciences Pharmaceutiques et Biologiques, Laboratory de Chemie Organic, 4, Avenue de L'Observatoire, 75270 Paris Cedex 06

Ditercalinium, Flexi-Di and D232 are members of a family of DNA bis-intercalators that causes cell death in E. coli by inducing futile and abortive DNA repair. These three family members vary only in their linkers, which bind in the major groove of DNA. We have previously reported 3-D structures of ditercalinium and Flexi-Di bound to fragments of DNA. Here we report structures of complexes of D232 bound to DNA fragments d(CGTACG) and d(BrCGTABrCG). The piperidinium rings in the linker of D232 are separated by three methylene groups. This recently solved structures will aid us in testing our previous hypotheses (1) of a novel mechanism by which anti-tumor agents bend DNA, (2) that localized destabilization (inferred from unstacking of DNA bases) increases deformability of DNA, (3) that the activity of ditercalinium in E. coli is caused by excessive or unusual deformability of its DNA complexes, (4) that a recognition element of the (A)BC repair system is excessive or unusual deformability of damaged DNA, (5) that specific conformational restraints of the linker of ditercalinium lead to intrinsic asymmetry in its DNA complexes, (6) that ditercalinium complexes are dynamic, converting between degenerate states, and (7) that the unique activity of ditercalinium in mammalian systems is related to structural polymorphism and dynamic conversion between conformers.