Ligand-Induced Conformational Changes with Cation Ejection upon Binding to Human Telomeric DNA G-Quadruplexes

International audienceThe rational design of ligands targeting human telomeric DNA G‐q uadruplexes 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 differ-ent 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 de-termined 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+ re-moval. 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 under-go 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 inter-quartet cation