title: Ligand-induced conformational changes with cation ejection upon binding to human telomeric DNA G-quadruplexes.
abstract: The rational design of ligands targeting human telomeric DNA G-quadruplexes is a complex problem due to the structural polymorphism that these sequences can adopt in physiological conditions. Moreover, the ability of ligands to switch conformational equilibria between different G-quadruplex structures is often overlooked in docking approaches. Here, we demonstrate that three of the most potent G-quadruplex ligands (360A, Phen-DC3, and pyridostatin) induce conformational changes of telomeric DNA G-quadruplexes to an antiparallel structure (as determined by circular dichroism) containing only one specifically coordinated K(+) (as determined by electrospray mass spectrometry) and, hence, presumably only two consecutive G-quartets. Control ligands TrisQ, known to bind preferentially to hybrid than to antiparallel structures, and L2H2-6M(2)OTD, known not to disrupt the hybrid-1 structure, did not show such K(+) removal. Instead, binding of the cyclic oxazole L2H2-6M(2)OTD was accompanied by the uptake of one additional K(+). Also contrasting with telomeric G-quadruplexes, the parallel-stranded Pu24-myc G-quadruplex, to which Phen-DC3 is known to bind by end-stacking, did not undergo cation removal upon ligand binding. Our study therefore evidences that very affine ligands can induce conformational switching of the human telomeric G-quadruplexes to an antiparallel structure and that this conformational change is accompanied by removal of one interquartet cation.
authors.affiliation: IECB, ARNA Laboratory, University of Bordeaux , 33600 Pessac, France.
authors.forename: Adrien
authors.initials: A
authors.lastname: Marchand
authors.forename: Anton
authors.initials: A
authors.lastname: Granzhan
authors.forename: Keisuke
authors.initials: K
authors.lastname: Iida
authors.forename: Yamato
authors.initials: Y
authors.lastname: Tsushima
authors.forename: Yue
authors.initials: Y
authors.lastname: Ma
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nagasawa
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Teulade-Fichou
authors.forename: Valérie
authors.initials: V
authors.lastname: Gabelica
mesh_terms: D000634:Aminoquinolines / Q000378:metabolism / Q000494:pharmacology; D004247:DNA / Q000737:chemistry* / Q000378:metabolism*; D054856:G-Quadruplexes / Q000187:drug effects*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D010848:Picolinic Acids / Q000378:metabolism / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology; D011804:Quinolines / Q000378:metabolism / Q000494:pharmacology; D016615:Telomere / Q000378:metabolism*
chemical_list: C502660:2,6-N,N'-methyl-quinolinio-3-yl-pyridine dicarboxamide; D000634:Aminoquinolines; D008024:Ligands; D010848:Picolinic Acids; D011725:Pyridines; D011804:Quinolines; C567962:pyridostatin; D004247:DNA; D011188:Potassium