6L75

Crystal structure of d(GTGGGCCGAC)2 DNA duplex

Summary for 6L75

• Entry DOI: 10.2210/pdb6l75/pdb
• Descriptor: DNA (5'-D(P*GP*TP*GP*GP*GP*CP*CP*GP*AP*C)-3') (3 entities in total)
• Functional Keywords: a form dna, ggggcc motif, gc rich duplex, g4c2, dna
• Biological source: synthetic construct; More
• Total number of polymer chains: 2
• Total formula weight: 6091.99

Authors

Hou, M.H.,Satange, R.B.,Zeng, J.Y. (deposition date: 2019-10-31, release date: 2021-01-13, Last modification date: 2024-04-03)

Primary citation

Jhan, C.R.,Satange, R.,Wang, S.C.,Zeng, J.Y.,Horng, Y.C.,Jin, P.,Neidle, S.,Hou, M.H.
Targeting the ALS/FTD-associated A-DNA kink with anthracene-based metal complex causes DNA backbone straightening and groove contraction.
Nucleic Acids Res., 49:9526-9538, 2021

PubMed Abstract: The use of a small molecule compound to reduce toxic repeat RNA transcripts or their translated aberrant proteins to target repeat-expanded RNA/DNA with a G4C2 motif is a promising strategy to treat C9orf72-linked disorders. In this study, the crystal structures of DNA and RNA-DNA hybrid duplexes with the -GGGCCG- region as a G4C2 repeat motif were solved. Unusual groove widening and sharper bending of the G4C2 DNA duplex A-DNA conformation with B-form characteristics inside was observed. The G4C2 RNA-DNA hybrid duplex adopts a more typical rigid A form structure. Detailed structural analysis revealed that the G4C2 repeat motif of the DNA duplex exhibits a hydration shell and greater flexibility and serves as a 'hot-spot' for binding of the anthracene-based nickel complex, NiII(Chro)2 (Chro = Chromomycin A3). In addition to the original GGCC recognition site, NiII(Chro)2 has extended specificity and binds the flanked G:C base pairs of the GGCC core, resulting in minor groove contraction and straightening of the DNA backbone. We have also shown that Chro-metal complexes inhibit neuronal toxicity and suppresses locomotor deficits in a Drosophila model of C9orf72-associated ALS. The approach represents a new direction for drug discovery against ALS and FTD diseases by targeting G4C2 repeat motif DNA.

PubMed: 33836081
DOI: 10.1093/nar/gkab227

Experimental method

X-RAY DIFFRACTION (1.578 Å)