Mateja-Pluta Martyna, Błaszczyk Leszek, Bejger Magdalena, Nakatani Kazuhiko, Kiliszek Agnieszka
Institute of Bioorganic Chemistry, Polish Academy of Sciences, Z. Noskowskiego 12/14, 61-704, Poland.
Department of Regulatory Bioorganic Chemistry, SANKEN (The Institute of Scientific and Industrial Research), Osaka University, 8-1 Mihogaoka, Ibaraki 567-0047, Japan.
Nucleic Acids Res. 2025 Sep 5;53(17). doi: 10.1093/nar/gkaf924.
The naphthyridine carbamate dimer (NCD) is a small molecule that recognizes disease-related RNA containing UGGAA repeats associated with spinocerebellar ataxia type 31 (SCA 31) and alleviates the disease phenotype in vitro and in vivo. In this study, we use X-ray crystallography to elucidate the mode of NCD binding in detail. We determine the crystal structures of the RNA-NCD complex and a structure of unliganded RNA. The NCD interacts differently than in previously reported nuclear magnetic resonance structure, forming pseudo-canonical base pairs with guanosine residues located on the same RNA strand. Furthermore, in one of the complexes, the ligand is located between symmetry-related RNA molecules, exhibiting a molecular glue characteristics in crystal lattice formation. The comparison of RNA-NCD and ligand-free models allows the identification of structural changes in RNA upon ligand binding from A-form to Z-RNA-like form. These observations extend our understanding of the interactions between RNA and small compounds and can be useful as a reference model in the development of bioinformatics tools for RNA-ligand structure predictions.
萘啶氨基甲酸酯二聚体（NCD）是一种小分子，可识别含有与31型脊髓小脑共济失调（SCA 31）相关的UGGAA重复序列的疾病相关RNA，并在体外和体内减轻疾病表型。在本研究中，我们使用X射线晶体学详细阐明NCD的结合模式。我们确定了RNA-NCD复合物的晶体结构和未结合配体的RNA结构。NCD的相互作用方式与先前报道的核磁共振结构不同，它与位于同一RNA链上的鸟苷残基形成假规范碱基对。此外，在其中一种复合物中，配体位于对称相关的RNA分子之间，在晶格形成中表现出分子胶水的特性。RNA-NCD模型与无配体模型的比较使我们能够识别配体结合后RNA从A形式到Z-RNA样形式的结构变化。这些观察结果扩展了我们对RNA与小分子化合物之间相互作用的理解，并可作为开发用于RNA-配体结构预测的生物信息学工具的参考模型。
