title: The use of conformationally rigid nucleoside probes to study the role of sugar pucker and nucleobase orientation in the thrombin binding aptamer.
abstract: Thrombin binding aptamers (TBAs) incorporating North-/South-deoxyguanosines built on the rigid bicyclo[3.1.0]hexane template were synthesized. Individual 2'-deoxyguanosines at positions dG14 and dG15 of the aptamer were replaced by these analogues where the North/anti and South/syn conformational states were confined. The substitution at position 14 with a locked South/syn-dG nucleoside produced an aptamer with the same stability and global structure as the innate, unmodified one. Replacing position 15 with the same South/syndG nucleoside induced a strong destabilization of the aptamer, while the antipodal North/anti-dG nucleoside was less destabilizing. Remarkably, the insertion of a North/anti-dG nucleoside at position 14, where both pseudosugar conformation and glycosyl torsion angle are opposite with respect to the native structure, led to the complete disruption of the G-tetraplex structure as detected by NMR and confirmed by extensive molecular dynamics simulations.
authors.affiliation: Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA.
authors.forename: Hisao
authors.initials: H
authors.lastname: Saneyoshi
authors.forename: Stefania
authors.initials: S
authors.lastname: Mazzini
authors.forename: Anna
authors.initials: A
authors.lastname: Aviñó
authors.forename: Guillem
authors.initials: G
authors.lastname: Portella
authors.forename: Carlos
authors.initials: C
authors.lastname: González
authors.forename: Modesto
authors.initials: M
authors.lastname: Orozco
authors.forename: Victor E
authors.initials: VE
authors.lastname: Marquez
authors.forename: Ramon
authors.initials: R
authors.lastname: Eritja
mesh_terms: D052157:Aptamers, Nucleotide / Q000737:chemistry*; D003849:Deoxyguanosine / Q000737:chemistry; D006586:Hexanes / Q000737:chemistry; D009690:Nucleic Acid Conformation; D009705:Nucleosides / Q000737:chemistry*
chemical_list: D052157:Aptamers, Nucleotide; D006586:Hexanes; D009705:Nucleosides; C081676:thrombin aptamer; D003849:Deoxyguanosine