Structure of the Human Telomere in K+ Solution: A Stable Basket-Type G-Quadruplex with Only Two G-Tetrad Layers

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Abstract
Previously, it has been reported that human telomeric DNA sequences could adopt in different experimental conditions four different intramolecular G-quadruplexes each involving three G-tetrad layers, namely, Na+ solution antiparallel-stranded basket form, K+ crystal parallel-stranded propeller form, K+ solution (3 + 1) Form 1, and K+ solution (3 + 1) Form 2. Here we present a new intramolecular G-quadruplex adopted by a four-repeat human telomeric sequence in K+ solution (Form 3). This structure is a basket-type G-quadruplex with only two G-tetrad layers: loops are successively edgewise, diagonal, and edgewise; glycosidic conformations of guanines are syn•syn•anti•anti around each tetrad. Each strand of the core has both a parallel and an antiparallel adjacent strands; there are one narrow, one wide, and two medium grooves. Despite the presence of only two G-tetrads in the core, this structure is more stable than the three-G-tetrad intramolecular G-quadruplexes previously observed for human telomeric sequences in K+ solution. Detailed structural elucidation of Form 3 revealed extensive base pairing and stacking in the loops capping both ends of the G-tetrad core, which might explain the high stability of the structure. This novel structure highlights the conformational heterogeneity of human telomeric DNA. It establishes a new folding principle for G-quadruplexes and suggests new loop sequences and structures for targeting in human telomeric DNA.

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