DSSR-PyMOL cartoon-block schematics: PDB entry 6m5j

PDB-id

6m5j; DSSR-derived features in text and JSON formats

Class

DNA

Method

X-ray (1.65 Å)

Summary

U shaped head to head four-way junction in d(ttctgctgctgaa-ttctgcagctgaa) sequence

Reference

Chien CM, Wu PC, Satange R, Chang CC, Lai ZL, Hagler LD, Zimmerman SC, Hou MH (2020): "Structural Basis for Targeting T:T Mismatch with Triaminotriazine-Acridine Conjugate Induces a U-Shaped Head-to-Head Four-Way Junction in CTG Repeat DNA." J.Am.Chem.Soc., 142, 11165-11172. doi: 10.1021/jacs.0c03591.

Abstract

The potent DNA-binding compound triaminotriazine-acridine conjugate (Z1) functions by targeting T:T mismatches in CTG trinucleotide repeats that are responsible for causing neurological diseases such as myotonic dystrophy type 1, but its binding mechanism remains unclear. We solved a crystal structure of Z1 in a complex with DNA containing three consecutive CTG repeats with three T:T mismatches. Crystallographic studies revealed that direct intercalation of two Z1 molecules at both ends of the CTG repeat induces thymine base flipping and DNA backbone deformation to form a four-way junction. The core of the complex unexpectedly adopts a U-shaped head-to-head topology to form a crossover of each chain at the junction site. The crossover junction is held together by two stacked G:C pairs at the central core that rotate with respect to each other in an X-shape to form two nonplanar minor-groove-aligned G·C·G·C tetrads. Two stacked G:C pairs on both sides of the center core are involved in the formation of pseudo-continuous duplex DNA. Four metal-mediated base pairs are observed between the N7 atoms of G and Co_II, an interaction that strongly preserves the central junction site. Beyond revealing a new type of ligand-induced, four-way junction, these observations enhance our understanding of the specific supramolecular chemistry of Z1 that is essential for the formation of a noncanonical DNA superstructure. The structural features described here serve as a foundation for the design of new sequence-specific ligands targeting mismatches in the repeat-associated structures.