title: Structure of a G-quadruplex-ligand complex.
abstract: Stabilisation of G-quadruplex structures formed from telomeric DNA, by means of quadruplex-selective ligands, is a means of inhibiting the telomerase enzyme from catalysing the synthesis of telomeric DNA repeats. In order to understand the molecular basis of ligand-quadruplex recognition, the crystal structure has been determined of such a complex, at 1.75A resolution. This complex is between a dimeric antiparallel G-quadruplex formed from the Oxytricha nova telomeric DNA sequence d(GGGGTTTTGGGG), and a di-substituted aminoalkylamido acridine compound. The structure shows that the acridine moiety is bound at one end of the stack of G-quartets, within one of the thymine loops. It is held in place by a combination of stacking interactions and specific hydrogen bonds with thymine bases. The stability of the ligand in this binding site has been confirmed by a 2ns molecular dynamics simulation.
authors.affiliation: Cancer Research UK Biomolecular Structure Group, The School of Pharmacy, University of London, 29-39 Brunswick Square, WC1N 1AX, London, UK.
authors.forename: Shozeb M
authors.initials: SM
authors.lastname: Haider
authors.forename: Gary N
authors.initials: GN
authors.lastname: Parkinson
authors.forename: Stephen
authors.initials: S
authors.lastname: Neidle
mesh_terms: D000166:Acridines / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D054856:G-Quadruplexes; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D016813:Oxytricha / Q000235:genetics; D011759:Pyrrolidines / Q000737:chemistry* / Q000378:metabolism*; D016615:Telomere / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: C471713:3,6-bis-(3-pyrrolidinopropionamide)acridine; D000166:Acridines; D008024:Ligands; D011759:Pyrrolidines; D004247:DNA