SOLUTION STRUCTURE OF THE HUMAN TELOMERIC REPEAT D[AG(3)(T(2)AG(3))3]G-TETRAPLEX

Background: Repeats of G, sequences are detected as single strand over hangs at the ends of eukaryotic chromosomes together with associated b inding proteins. Such telomere sequences have been implicated in the r eplication and maintenance of chromosomal termini. They may also media te chromosomal organization and association during meiosis and mitosis . Results: We have determined the three-dimensional solution structure of the human telomere sequence, d[AG(3)(T(2)AG(3))(3)] in Na+-contain ing solution using a combined NMR, distance geometry and molecular dyn amics approach (including relaxation matrix refinement). The sequence, which contains four AG(3) repeats, folds intramolecularly into a G-te traplex stabilized by three stacked G-tetrads which are connected by t wo lateral loops and a central diagonal loop. Of the four grooves chat are formed, one is wide, two are of medium width and one is narrow. T he alignment of adjacent G-G-G segments in parallel generates the two grooves of medium width whilst the antiparallel arrangement results in one wide and one narrow groove. Three of the four adenines stack on t op of adjacent G-tetrads while the majority of the thymines sample mul tiple conformations.Conclusions: The availability of the d[AG(3)(T(2)A G(3))(3)] solution structure containing four AG(3) human telomeric rep eats should permit the rational design of ligands that recognize and b ind with specificity and affinity to the individual grooves of the G-t etraplex, as well as to either end containing the diagonal and lateral loops. Such ligands could modulate the equilibrium between folded G-t etraplex structures and their unfolded extended counterparts.