NMR determination of the 2:1 binding complex of naphthyridine carbamate dimer (NCD) and CGG/CGG triad in double-stranded DNA

  • Nucleic Acids Res. 2022 Sep 23;50(17):9621-9631. doi: 10.1093/nar/gkac740.
Takeshi Yamada  1 ,  Kyoko Furuita  2 ,  Shuhei Sakurabayashi  1  2 ,  Makoto Nomura  3 ,  Chojiro Kojima  2  4 ,  Kazuhiko Nakatani  1
Affiliations
  • 1. Department of Regulatory Bioorganic Chemistry, SANKEN, Osaka University, 8-1 Mihogaoka, Ibaraki 567-0047, Japan.
  • 2. Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
  • 3. Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma 630-0192, Japan.
  • 4. Graduate School of Engineering Science, Yokohama National University, 79-5 Tokiwadai, Hodogaya-ku, Yokohama 240-8501, Japan.
PMID: 36095126 DOI: 10.1093/nar/gkac740
Abstract

Trinucleotide repeat (TNR) diseases are caused by the aberrant expansion of CXG (X = C, A, G and T) sequences in genomes. We have reported two small molecules binding to TNR, NCD, and NA, which strongly bind to CGG repeat (responsible sequence of fragile X syndrome) and CAG repeat (Huntington's disease). The NMR structure of NA binding to the CAG/CAG triad has been clarified, but the structure of NCD bound to the CGG/CGG triad remained to be addressed. We here report the structural determination of the NCD-CGG/CGG complex by NMR spectroscopy and the comparison with the NA-CAG/CAG complex. While the NCD-CGG/CGG structure shares the binding characteristics with that of the NA-CAG/CAG complex, a significant difference was found in the overall structure caused by the structural fluctuation at the ligand-bound site. The NCD-CGG/CGG complex was suggested in the equilibrium between stacked and kinked structures, although NA-CAG/CAG complex has only the stacked structures. The dynamic fluctuation of the NCD-CGG/CGG structure at the NCD-binding site suggested room for optimization in the linker structure of NCD to gain improved affinity to the CGG/CGG triad.

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