Zα Domain of ADAR1 Binds to an A-Form-like Nucleic Acid Duplex with Low Micromolar Affinity

Biochemistry, Journal Year: 2024, Volume and Issue: 63(6), P. 777 - 787

Published: March 4, 2024

The left-handed Z-conformation of nucleic acids can be adopted by both DNA and RNA when bound Zα domains found within a variety viral innate immune response proteins. While Z-form adoption is preferred certain sequences, such as the commonly studied (CpG)n repeats, has been reported to bind wide range sequence contexts. Studying how interacts with B-/A-form helices prior their conversion challenging binding coincides adoption. Here, we fromHomo sapiens ADAR1 locked "A-type" version (CpG)3 construct (LNA (CpG)3) where sugar pucker into C3′-endo/C2′-exo conformation, which prevents duplex from adopting alternating C2′/C3′-endo puckers in Z-conformation. Using NMR other biophysical techniques, find that ZαADAR1 binds LNA using similar interface for binding, dissociation constant (KD) ∼4 μM. In contrast Z-DNA/Z-RNA, two every 6 bp stretch, our data suggests multiple molecules, indicating completely different mode. Because relatively tightly non-Z-form model, its B/A-form may need considered experiments are carried out attempt identify targets domains. use constructs beneficial negative controls needed.

Language: Английский

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Intracellular nonenzymatic in situ growth of layered nanosheet DNA architectures based on palindrome-chained dumbbell probes for miRNA imaging

Talanta, Journal Year: 2024, Volume and Issue: 277, P. 126333 - 126333

Published: June 7, 2024

Language: Английский

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Formation of left-handed helices by C2′-fluorinated nucleic acids under physiological salt conditions

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 52(13), P. 7414 - 7428

Published: June 13, 2024

Abstract Recent findings in cell biology have rekindled interest Z-DNA, the left-handed helical form of DNA. We report here that two minimally modified nucleosides, 2′F-araC and 2′F-riboG, induce formation Z-form under low ionic strength. show oligomers entirely made these nucleosides exclusively produce duplexes bind to Zα domain ADAR1. The effect nucleotides is so dramatic are only species observed 10 mM sodium phosphate buffer neutral pH, no B-form at any temperature. Hence, contrast other studies reporting Z/B-form equilibria by a preference for purine glycosidic angles syn, our NMR computational work revealed sequential 2′F…H2N intramolecular 3′H…N3′ interactions stabilize helix. equilibrium between B- Z- forms slow 19F time scale (≥ms), each conformation exhibited unprecedented chemical shift differences signals. This observation led reliable estimation relative population B Z enabled us monitor B–Z transitions different conditions. unique features 2′F-modified DNA should thus be valuable addition existing techniques specific detection new Z-binding proteins ligands.

Language: Английский

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Oligonucleotides Containing 8,1′‐Ethano‐2′‐deoxyadenosine: Synthesis and Properties

European Journal of Organic Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 8, 2024

Abstract Oligonucleotides containing 8,1′‐ethano‐2′‐deoxyadenosine (ethano‐dA) were synthesized in which the adenine base ( eth A) is fixed syn conformation. Ethano‐dA phosphoramidite was by using a 1,5‐hydrogen‐atom transfer/radical cyclization process and introduced into oligonucleotides, successfully obtained employing 4,4′‐dimethoxytrityl‐off synthesis mode. The duplex‐forming ability of oligonucleotides ethano‐dA evaluated. In antiparallel Watson–Crick duplex, A formed stable pairs with thymine guanine, two Hoogsteen‐type hydrogen bonds could be formed. By contrast, parallel Hoogsteen duplex A:thymine pair showed thermal stability comparable to that natural adenine:thymine because can form Watson–Crick‐type bonds. These results indicated may helpful for elucidating function bases through conformation DNA.

Language: Английский

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RNA Structure: Past, Future, and Gene Therapy Applications

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 26(1), P. 110 - 110

Published: Dec. 26, 2024

First believed to be a simple intermediary between the information encoded in deoxyribonucleic acid and that functionally displayed proteins, ribonucleic (RNA) is now known have many functions through its abundance intricate, ubiquitous, diverse, dynamic structure. About 70–90% of human genome transcribed into protein-coding noncoding RNAs as main determinants along with regulatory sequences cellular populational biological diversity. From nucleotide sequence or primary structure, Watson–Crick pairing self-folding secondary compaction via longer distance non-Watson–Crick interactions tertiary RNA other biopolymers quaternary metabolites biomolecules quinary structure plays critical role RNA’s lifecycle from transcription decay processes. In contrast success 3-dimensional protein prediction using AlphaFold, beyond structures remains challenging. However, approaches involving machine learning artificial intelligence, sequencing modifications, structural analyses at single-cell intact tissue levels, among others, provide an optimistic outlook for continued development refinement RNA-based applications. Here, we highlight those gene therapy.

Language: Английский

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