NMR-Based Rational Drug Design of G:G Mismatch DNA Binding Ligand Trapping Transient Complex via Disruption of a Key Allosteric Interaction

Small molecules that bind to mismatched DNA have been applied in various fields, including nanotechnology, bioimaging, and therapeutics. However, the intrinsic dynamic nature of mismatched DNA complicates the prediction of structural changes upon ligand binding, hindering rational ligand design. In...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Journal of the American Chemical Society Jg. 147; H. 17; S. 14254 - 14269
Hauptverfasser: Sakurabayashi, Shuhei, Furuita, Kyoko, Yamada, Takeshi, Sugiura, Noriaki, Nomura, Makoto, Nakane, Takanori, Kawamoto, Akihiro, Kurisu, Genji, Miyanoiri, Yohei, Fujiwara, Toshimichi, Nakatani, Kazuhiko, Kojima, Chojiro
Format: Journal Article
Sprache:Englisch
Veröffentlicht: WASHINGTON Amer Chemical Soc 17.04.2025
Schlagworte:
Allosteric Site
Base Pair Mismatch
Chemistry
Chemistry, Multidisciplinary
DNA - chemistry
Drug Design - methods
Kinetics
Ligands
Nuclear Magnetic Resonance, Biomolecular
Physical Sciences
Science & Technology
Thermodynamics
REPAIR
INSTABILITY
RECOGNITION
GUANINE-GUANINE MISMATCHES
STABILITY
TRIPLET REPEATS
MECHANISMS
TRINUCLEOTIDE REPEATS
WATER SUPPRESSION
PAIRS
ISSN:0002-7863, 1520-5126, 1520-5126
Online-Zugang:Weitere Angaben
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung:Small molecules that bind to mismatched DNA have been applied in various fields, including nanotechnology, bioimaging, and therapeutics. However, the intrinsic dynamic nature of mismatched DNA complicates the prediction of structural changes upon ligand binding, hindering rational ligand design. In this study, NMR was used for structure-based drug design, with a focus on the G:G mismatch binder ND and the structural dynamics of the DNA-ND complex. Through comprehensive NMR analysis with isotope labeling, two complex structures, the transient and stable complexes, were successfully determined. The nucleobase flip-outs and the distortion of the phosphate backbone of the complex structures were characterized by residual dipolar coupling (RDC) and 31P NMR, respectively. The RDC-refined stable complex structure suggested that the ligand linker-nucleobase interaction allosterically regulates a structural transition. This interaction was experimentally validated by 1H-15N HSQC spectra using a 15N-labeled ligand. Disruption of this key allosteric interaction facilitated the design of a new ligand, sND, that traps the transient complex structure. In conclusion, comprehensive NMR analysis using a weak binder aids in designing nucleic acid-binding ligands based on transient complex structures.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0002-7863
1520-5126
1520-5126
DOI:10.1021/jacs.4c17538