Structural Studies on Dinuclear Ruthenium(II) Complexes That Bind Diastereoselectively to an Antiparallel Folded Human Telomere Sequence
authors Wilson, T; Costa, PJ; Felix, V; Williamson, MP; Thomas, JA
nationality International
journal JOURNAL OF MEDICINAL CHEMISTRY
keywords G-QUADRUPLEX DNA; INTRAMOLECULAR G-QUADRUPLEX; PARTICLE MESH EWALD; AMBER FORCE-FIELD; K+ SOLUTION; CRYSTAL-STRUCTURE; METAL-COMPLEXES; MOLECULAR-DYNAMICS; DRUG RECOGNITION; PROMOTER REGION
abstract We report DNA binding studies of the dinuclear ruthenium ligand [{Ru(phen)(2)}(2)tpphz](4+) in enantiomerically pure forms. As expected from previous studies of related complexes, both isomers bind with similar affinity to B-DNA and have enhanced luminescence. However, when tested against the G-quadruplex from human telomeres (which we show to form an antiparallel basket structure with a diagonal loop across one end), the Lambda Lambda isomer binds approximately 40 times more tightly than the Delta Delta, with a stronger luminescence. NMR studies show that the complex binds at both ends of the quadruplex. Modeling studies, based on experimentally derived restraints obtained for the closely related [{Ru(bipy)(2)}(2)tpphz](4+), show that the Lambda Lambda isomer fits neatly under the diagonal loop, whereas the Delta Delta isomer is unable to bind here and binds at the lateral loop end. Molecular dynamics simulations show that the Delta Delta isomer is prevented from binding under the diagonal loop by the rigidity of the loop. We thus present a novel enantioselective binding substrate for antiparallel basket G-quadruplexes, with features that make it a useful tool for quadruplex studies.
publisher AMER CHEMICAL SOC
issn 0022-2623
year published 2013
volume 56
issue 21
beginning page 8674
ending page 8683
digital object identifier (doi) 10.1021/jm401119b
web of science category Chemistry, Medicinal
subject category Pharmacology & Pharmacy
unique article identifier WOS:000327111100035
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journal impact factor 6.253
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