<br>CTG 三核苷酸重复形成的链内发夹的高分辨率 NMR 结构,ACS Chemical Neuroscience

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CTG 三核苷酸重复形成的链内发夹的高分辨率 NMR 结构
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2024-02-06 , DOI: 10.1021/acschemneuro.3c00769
Liqi Wan _{1,

2} , Axin He _{1,

2} , Jinxing Li ₃ , Pei Guo ₂ , Da Han _{1,

2}

Affiliation

CAG 和 CTG 三核苷酸重复扩增会导致 10 多种人类神经退行性疾病。由三核苷酸重复形成的链内发夹有助于重复扩增，使它们成为潜在的药物靶点。 CAG 和 CTG 发夹的高分辨率结构测定是帮助药物开发的长期目标，但由于重复序列固有的构象灵活性，这一目标尚未实现。我们使用核磁共振（NMR）光谱研究了CTG发夹的溶液结构，发现具有夹紧GC碱基对的四个CTG重复能够形成稳定的发夹结构。我们确定了dG(CTG) ₄ C发夹的第一个溶液NMR结构，并破译了TGCT四环的I型折叠几何结构，其中两个胸腺嘧啶残基形成T·T闭环碱基对，前三个环残基连续堆叠。我们进一步揭示了 CTG 发夹可以通过小分子配体结合和稳定，并且这种结合会干扰含有 CTG 重复序列的 DNA 模板的复制。我们确定的高分辨率结构为研究天然CTG发夹和配体之间的分子相互作用奠定了重要基础，并有利于三核苷酸重复扩增疾病的药物开发。

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High-Resolution NMR Structures of Intrastrand Hairpins Formed by CTG Trinucleotide Repeats

The CAG and CTG trinucleotide repeat expansions cause more than 10 human neurodegenerative diseases. Intrastrand hairpins formed by trinucleotide repeats contribute to repeat expansions, establishing them as potential drug targets. High-resolution structural determination of CAG and CTG hairpins poses as a long-standing goal to aid drug development, yet it has not been realized due to the intrinsic conformational flexibility of repetitive sequences. We herein investigate the solution structures of CTG hairpins using nuclear magnetic resonance (NMR) spectroscopy and found that four CTG repeats with a clamping G-C base pair was able to form a stable hairpin structure. We determine the first solution NMR structure of dG(CTG)₄C hairpin and decipher a type I folding geometry of the TGCT tetraloop, wherein the two thymine residues form a T·T loop-closing base pair and the first three loop residues continuously stack. We further reveal that the CTG hairpin can be bound and stabilized by a small-molecule ligand, and the binding interferes with replication of a DNA template containing CTG repeats. Our determined high-resolution structures lay an important foundation for studying molecular interactions between native CTG hairpins and ligands, and benefit drug development for trinucleotide repeat expansion diseases.

更新日期：2024-02-06

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