| Abstract
| - Maintenance of telomere integrity is a hallmark of human cancer, and the single-stranded 3‘ends of telomeric DNA are targets for small-molecule anticancer therapies. We report here the crystalstructure of a bimolecular human telomeric quadruplex, of the sequence d(TAGGGTTAGGG), in a complexwith the quadruplex-binding ligand 5,10,15,20-tetrakis(N-methyl-4-pyridyl)porphyrin (TMPyP4) to aresolution of 2.09 Å. The DNA quadruplex topology is parallel-stranded with external double-chain-reversal propeller loops, consistent with previous structural determinations. The porphyrin molecules bindby stacking onto the TTA nucleotides, either as part of the external loop structure or at the 5‘ region ofthe stacked quadruplex. This involves stacked on hydrogen-bonded base pairs, formed from thosenucleotides not involved in the formation of G-tetrads, and there are thus no direct ligand interactionswith G-tetrads. This is in accord with the relative nonselectivity by TMPyP4 for quadruplex DNAs comparedto duplex DNA. Porphyrin binding is achieved by remodeling of loops compared to the ligand-freestructures. Implications for the design of quadruplex-binding ligands are discussed, together with a modelfor the formation of anaphase bridges, which are observed following cellular treatment with TMPyP4.
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