The first crystal structure of a drug (daunomycin) bound to a parallel-stranded intermolecular telomeric G4 quadruplex (d(TGGGGT)4) has been determined to high resolution. A planar assemblage of three daunomycin molecules stacks onto the 5' end of the G4 column, with the daunosamine substituents occupying three of the four quadruplex grooves. The surface area of the terminal G-quartet in this parallel DNA quadruplex, presently occupied by three daunomycins, is sufficiently large that it could easily accommodate other potential telomerase inhibitors such as substituted porphyrins or telomestatin.

Telomeres occur as multiple repeats of guanine-rich segments at the 3' ends of chromosomes.Most of the telomeric region is double-helical, but a singlestranded overhang protrudes at the extreme 3' terminus, and the guanines in this region can associate strongly to form stacked G4 quadruplexes.There is intense current interest in designing intercalating drug molecules to act as inhibitors of the enzyme telomerase which protects tumor cells against telomere loss during replication.Despite this interest, little is presently known about quadruplex assemblies in vivo, and the only crystal structures which have been reported are for the uncomplexed G4-quadruplexes d(GGGGTTTTGGGG) and d(TGGGGT).We report the first structure determination of a crystal containing a drug molecule bound to a G4 quadruplex -the anti-cancer agent Daunomycin complexed with the telomeric sequence d(TGGGGT).The crystal is monoclinic, space group C2, with a = 53.078Å, b = 47.239Å, c = 31.914Å, β = 119.80°.Intensity data were collected at SSRL to 1.17 Å resolution.The asymmetric unit contains four d(TGGGGT) strands in a G4 quadruplex stack, three daunomycin molecules, and three Na cations.The daunomycins are mutually coplanar, but they do not intercalate into the guanine core of the quadruplex.Instead, they make weak ππ stacking interactions with guanines at one end of the quadruplex and stronger ππ interactions with symmetry-related daunomycins from neighbouring asymmetric units.The aliphatic moieties of the daunomycins project into three of the four grooves spiraling around the G4 stack.The overall crystal architecture is highly asymmetric.