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
- 1 June 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 142 (25), 11165-11172
- https://doi.org/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 CoII, 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.Keywords
Funding Information
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR069645)
- Ministry of Science and Technology, Taiwan (MOST 106-2628-M-005-001-MY3)
This publication has 37 references indexed in Scilit:
- The structural basis of actinomycin D–binding induces nucleotide flipping out, a sharp bend and a left-handed twist in CGG triplet repeatsNucleic Acids Research, 2013
- Features and development of CootActa Crystallographica Section D-Biological Crystallography, 2010
- A simple ligand that selectively targets CUG trinucleotide repeats and inhibits MBNL protein bindingProceedings of the National Academy of Sciences, 2009
- Mechanisms and functions of DNA mismatch repairCell Research, 2007
- A short history of SHELXActa Crystallographica Section A Foundations of Crystallography, 2007
- Ligand Bridging of the DNA Holliday Junction: Molecular Recognition of a Stacked‐X Four‐Way Junction by a Small MoleculeAngewandte Chemie-International Edition, 2007
- Mechanisms of Disease: DNA repair defects and neurological diseaseNature Clinical Practice Neurology, 2007
- Dynamic roles for G4 DNA in the biology of eukaryotic cellsNature Structural & Molecular Biology, 2006
- The crystal structures of psoralen cross-linked DNAs: drug-dependent formation of Holliday junctionsJournal of Molecular Biology, 2001
- Crystal structure of double-stranded DNA containing the major adduct of the anticancer drug cisplatinNature, 1995