6M5J

U shaped head to head four-way junction in d(TTCTGCTGCTGAA/TTCTGCAGCTGAA) sequence

Summary for 6M5J

• Entry DOI: 10.2210/pdb6m5j/pdb
• Descriptor: DNA (5'-D(P*TP*TP*CP*TP*GP*CP*TP*GP*CP*TP*GP*AP*A)-3'), DNA (5'-D(P*TP*TP*CP*TP*GP*CP*AP*GP*CP*TP*GP*AP*A)-3'), COBALT (II) ION, ... (5 entities in total)
• Functional Keywords: t:t mismatch, ctg repeat, four-way junction, triaminotriazine-acridine conjugate, dna
• Biological source: synthetic construct; More
• Total number of polymer chains: 4
• Total formula weight: 17830.73

Authors

Hou, M.H.,Chien, C.M.,Satange, R.B. (deposition date: 2020-03-11, release date: 2020-07-15, Last modification date: 2023-11-29)

Primary citation

Chien, C.M.,Wu, P.C.,Satange, R.,Chang, C.C.,Lai, Z.L.,Hagler, L.D.,Zimmerman, S.C.,Hou, M.H.
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, 2020

PubMed 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, 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.

PubMed: 32478511
DOI: 10.1021/jacs.0c03591

Experimental method

X-RAY DIFFRACTION (1.65 Å)