STRUCTURE OF A DICATIONIC MONOIMIDAZOLE LEXITROPSIN BOUND TO DNA

An X-ray crystal structure has been solved of the complex of a dicatio nic lexitropsin with a B-DNA duplex of sequence CGCGAATTCGCG. The lexi tropsin is identical to netropsin except for replacement of the first methylpyrrole ring by methylimidazole, converting a =CH- to =N-. Cryst als are isomorphous with those of the DNA dodecamer in the absence of drug. Although the =N- for =CH- substitution was intended to make that locus on the drug molecule compatible with a G . C base pair, electro static attraction for the two cationic ends of the drug predominates, and this lexitropsin binds to the same central AATT site as does the p arent netropsin. But unlike netropsin, this lexitropsin exhibits end-f or-end disorder in the crystal. Both orientations were refined separat ely to completion. Final residual errors at 2.25 Angstrom resolution f or the 2358 reflections above 2 sigma in F are R = 0.165 for one orien tation (LexA) with 37 water molecules and 0.164 for the inverted drug orientation (LexB) with 40 water molecules. This molecular disorder is probably attributable to a weakening of binding to the AATT site occa sioned by the imidazole-for-pyrrole substitution.