Structural Basis for the Identification of an i-Motif Tetraplex Core with a Parallel-Duplex Junction as a Structural Motif in CCG Triplet Repeats.

CCG triplet repeats can fold into tetraplex structures, which are associated with the expansion of (CCG) _n trinucleotide sequences in certain neurological diseases. These structures are stabilized by intertwining i-motifs. However, the structural basis for tetraplex i-motif formation in CCG triplet repeats remains largely unknown. We report the first crystal structure of a CCG-repeat sequence, which shows that two dT(CCG)₃A strands can associate to form a tetraplex structure with an i-motif core containing four C:C⁺ pairs flanked by two G:G homopurine base pairs as a structural motif. The tetraplex core is attached to a short parallel-stranded duplex. Each hairpin itself contains a central CCG loop in which the nucleotides are flipped out and stabilized by stacking interactions. The helical twists between adjacent cytosine residues of this structure in the i-motif core have an average value of 30°, which is greater than those previously reported for i-motif structures. [ABSTRACT FROM AUTHOR]