Christine M. Nunn

DNA minor groove recognition of a non-self-complementary AT-rich sequence by a tris-benzimidazole ligand.

The crystal structure of the non-self-complementary dodecamer DNA duplex formed by d(CG[5BrC]ATAT-TTGCG) and d(CGCAAATATGCG) has been solved to 2.3 A resolution, together with that of its complex with the tris-benzimidazole minor groove binding ligand TRIBIZ. The inclusion of a bromine atom on one strand in each structure enabled the possibility of disorder to be discounted. The native structure has an exceptional narrow minor groove, of 2.5-2.6 A in the central part of the A/T region, which is increased in width by approximately 0.8 A on drug binding. The ligand molecule binds in the central part of the sequence. The benzimidazole subunits of the ligand participate in six bifurcated hydrogen bonds with A:T base pair edges, three to each DNA strand. The presence of a pair of C-H...O hydrogen bonds has been deduced from the close proximity of the pyrrolidine group of the ligand to the TpA step in the sequence.

Crystal Structure of γ‐Oxapentamidine Complexed with d(CGCGAATTCGCG)2

The crystal structure of the complex of γ-oxapentamidine and the DNA dodecamer d(CGCGAATTCGCG)2 has been determined to a resolution of 0.22 nm and an R factor of 18.9%. The γ-oxapentamidine ligand interacts with the dodecamer by classic minor groove binding via interactions within the Arich region of the minor groove. A chain of solvent molecules lies along the mouth of the minor groove on the outside of the bound ligand. The structural details of the complex are discussed and compared with the closely analogous complex with pentamidine bound to the same dodecamer [Edwards, K. J., Jenkins, T. C. & Neidle, S. (1992) Biochemistry 31, 7104–7109]. The amidinium groups of the ligand do not hydrogen bond to bases, but are in close contact with O4′ sugar ring atoms. This in part explains the reduced DNA binding affinity of this ligand compared to pentamidine.

Crystal structures of nucleic acids and their drug complexes

The proposal for the structure of the DNA double helix in 1953 is generally considered to be the point at which genetic phenomena started to be understandable in molecular and chemical terms. Indeed Watson and Crick were themselves directly dependent for their success on the chemical knowledge of nucleotides from the work of Todd and his school, as well as relying heavily on X-ray cystallographic studies of nucleobases and nuclcosides.

A model for the [C+-G⋅C]n triple helix derived from observation of the C+-G⋅C base triplet in a crystal structure

A molecular modelling study on the [C+‐G⋅C]n triple helix is reported. We have observed the C+‐G⋅C base triplet in the crystal structure of an oligonucleotide‐drug complex, between the minor‐groove drug netropsin and the decanucleotide d(CGCAATTGCG)2. The complex was crystallised at pH 7.0, but the crystal structure, at a resolution of 2.4 Å, shows that a terminal cytosine has become protonated and participates in a parallel C+‐G⋅C base triplet. The structure of this triplet and its associated sugar‐phosphate backbones have been energy‐refined and then used to generate a triple helix. This has characteristics of the B‐type family of DNA structures for two strands, with the third, the C+ strand, having backbone conformations closer to the A family.

Crystal structure of d(AGGBrCATGCCT): implications for cobalt hexammine binding to DNA

The crystal structure of the DNA decamer d(AGGBrCATGCCT) has been determined to a resolution of 2.0 A and R factor of 19.6%. Crystals of d(AGGBrCATGCCT) were grown in the presence of cobalt hexammine but no cobalt hexammine ions are bound to the DNA structure. This contrasts with the recently determined crystal structure of d(AGGCATGCCT) which has a similar DNA conformation and cobalt hexammine ions bound directly to the DNA. Comparison with the structure of d(AGGCATGCCT) and appreciation of the crystal packing of this sequence leads to an understanding of how cobalt hexammine binding to DNA occurs and its role in determining DNA conformation.

Structure of the A-DNA Octamer d(GGCATGCC)

The crystal structure of the self-complementary DNA octamer d(GGCATGCC) has been determined to a resolution of 2.38 A and R factor of 17.1%. The structure is an A-DNA octamer duplex with Watson-Crick base pairing along its length. This sequence extends the investigation of octamer duplexes of the type d(GGX(4)CC) which assume P6(1) packing within the crystallographic unit cell. The A-DNA duplex is non-linear with a helix axis curvature of 7 degrees and bending towards the DNA minor groove. In view of the biological importance of protein recognition of some A-DNA sequences the minor-groove geometry and helix-axis curvature for this structure is compared with all others of the type d(GGXATXCC).