Maintenance of telomere integrity is a hallmark of human cancer, and the single-stranded 3’ ends of telomeric DNA are targets for small-molecule anti-cancer therapies. We report here the crystal structure of a bimolecular human telomeric bimolecular quadruplex, of sequence d(TAGGGTTAGGG) in a complex with the quadruplex-binding ligand 5,10,15,20-tetrakis(N-methyl-4-pyridyl)-porphyrin, (TMPyP4), and to a resolution of 2.09 Å. The DNA quadruplex topology, bound to a stabilizing ligand, is parallel-stranded with external double-chain-reversal propeller loops, consistent with previous structural determinations.. The porphyrin molecules bind by stacking onto the TTA nucleotides, either as part of the external loop structure, or at the 5’region of the stacked quadruplex. This involves stacked on hydrogen-bonded base pairs, formed from those nucleotides not involved in G-tetrad formation, and there are thus no direct drug interactions with G-tetrads. Porphyrin binding is achieved by remodelling of loops compared to the drug-free structures. Implications for the design of quadruplex-binding ligands are discussed, together with a model for the formation of anaphase bridges, which are observed following cellular treatment with TMPyP4.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA