Abstract
A DNA G‐quadruplex adopting a (3+1) hybrid structure was modified in two adjacent syn positions of the antiparallel strand with anti‐favoring 2′‐deoxy‐2′‐fluoro‐riboguanosine (FrG) analogues. The two substitutions promoted a structural rearrangement to a topology with the 5′‐terminal G residue located in the central tetrad and the two modified residues linked by a V‐shaped zero‐nucleotide loop. Strikingly, whereas a sugar pucker in the preferred north domain is found for both modified nucleotides, the FrG analogue preceding the V‐loop is forced to adopt the unfavored syn conformation in the new quadruplex fold. Apparently, a preferred C3′‐endo sugar pucker within the V‐loop architecture outweighs the propensity of the FrG analogue to adopt an anti glycosidic conformation. Refolding into a V‐loop topology is likewise observed for a sequence modified at corresponding positions with two riboguanosine substitutions. In contrast, 2′‐F‐arabinoguanosine analogues with their favored south‐east sugar conformation do not support formation of the V‐loop topology. Examination of known G‐quadruplexes with a V‐shaped loop highlights the critical role of the sugar conformation for this distinct structural motif.
Highlights
G-quadruplexes (G4s), formed by the stacking of guanine tetrads with their square-planar arrangement of hydrogenbonded guanine bases, have attracted growing interest in the past years due to their existence and potential regulatory role in vivo.[1,2,3] The remarkable variety of topologies as displayed by these four-stranded DNA structures[4,5] makes them promising tools for various technological applications.[6,7] G-quadruplexes can be composed of one, two, three, or four strands
The particular V-loop topology adopted by ODN(14,15) with two lateral loops followed by a V-loop and a propeller loop was reported for CHL1 and HPV52 sequences from the 5’-intron of the human CHL1 gene and the G-rich region of the human papillomavirus type 52.[11,21,22] Interestingly, HPV52 and ODN are derived from the same sequence encompassing five G-runs
The growing number of reported G-quadruplexes featuring a V-shaped loop attests to their potential significance as important structural elements in vivo and as powerful tools for technological applications that are based on quadruplex recognition
Summary
G-quadruplexes (G4s), formed by the stacking of guanine tetrads with their square-planar arrangement of hydrogenbonded guanine bases, have attracted growing interest in the past years due to their existence and potential regulatory role in vivo.[1,2,3] The remarkable variety of topologies as displayed by these four-stranded DNA structures[4,5] makes them promising tools for various technological applications.[6,7] G-quadruplexes can be composed of one (monomolecular), two (bimolecular), three (trimolecular), or four (tetramolecular) strands. Depending on the relative strand orientation as fixed by the type of loops in case of monomolecular G4s, topologies can be of a parallel, antiparallel, or hybrid type Additional features such as bulges,[8,9,10] capping structures like base triplets,[11,12,13,14,15,16,17] interrupted G-tracts and V-loops,[11,15,18,19,20,21,22,23,24] as well as interlocked G4s[18,25,26] further expand the topological landscape of these [b] Dr J.
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