PHASING IN DRUG-DNA SEQUENCE RECOGNITION: STRUCTURE OF A TRIS (BENZIMIDAZOLE) - DNA COMPLEX. Stephen Neidle, George R Clark⁺, Emily J Gray, Yu-Hua Li^# and Werner Leupin^#, The CRC Biomolecular Structure Unit, The Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK, ^#F. Hoffman-la-Roche Ltd, Preclinical Research Pharma Gene Technologies, CH-4002 Basel, Switzerland, ⁺Permanent address: Chemistry Department, University of Auckland, New Zealand

Effective recognition of a DNA sequence longer than ca 3-4 base pairs in length requires drug and base pairs to be in register along the complete length of the drug. We have studied this problem in the context of the crystal structure of a complex between a tris(benzimidazole) drug and the oligonucleotide duplex d(CGCAAATTTGCG)2. This has been determined to 2.2 Å resolution and refined to an R of 17.4%. The drug is bound in the minor groove region and covers ca 7? base pairs. There is an extensive set of hydrogen bonds between the imidazole rings and N₃/O₂ atoms of the A:T base pairs. These have exceptionally high propeller twists, and five out of the six have lost one of their two Watson-Crick hydrogen bonds; this is compensated for by a series of major-groove three-centre hydrogen bonds. The drug itself is highly twisted in order to achieve maximum hydrogen- bonding register with the A:T base pair edges. The DNA is deformed beyond what has been observed in other minor-groove drug crystal structures, with evidence of local helix unwinding and extension. These changes are necessary for effective DNA recognition of every benzimidazole sub-unit to take place, and thus for each to be in phase with base pairs.