Department of Chemistry, University of California, Davis, Davis, CA, USA.
Agios Pharmaceuticals, Cambridge, MA, USA.
Nat Commun. 2020 Oct 12;11(1):5130. doi: 10.1038/s41467-020-18862-2.
Adenosine Deaminases that act on RNA (ADARs) are enzymes that catalyze adenosine to inosine conversion in dsRNA, a common form of RNA editing. Mutations in the human ADAR1 gene are known to cause disease and recent studies have identified ADAR1 as a potential therapeutic target for a subset of cancers. However, efforts to define the mechanistic effects for disease associated ADAR1 mutations and the rational design of ADAR1 inhibitors are limited by a lack of structural information. Here, we describe the combination of high throughput mutagenesis screening studies, biochemical characterization and Rosetta-based structure modeling to identify unique features of ADAR1. Importantly, these studies reveal a previously unknown zinc-binding site on the surface of the ADAR1 deaminase domain which is important for ADAR1 editing activity. Furthermore, we present structural models that explain known properties of this enzyme and make predictions about the role of specific residues in a surface loop unique to ADAR1.
腺苷脱氨酶作用于 RNA（ADARs）是一种酶，可催化双链 RNA 中的腺苷向肌苷的转化，这是 RNA 编辑的一种常见形式。人类 ADAR1 基因突变已被证实可导致疾病，最近的研究还发现 ADAR1 是某些癌症的潜在治疗靶点。然而，由于缺乏结构信息，定义与疾病相关的 ADAR1 突变的机制影响以及合理设计 ADAR1 抑制剂的工作受到了限制。在这里，我们描述了高通量诱变筛选研究、生化特性分析和基于 Rosetta 的结构建模的结合，以鉴定 ADAR1 的独特特征。重要的是，这些研究揭示了 ADAR1 脱氨酶结构域表面上一个以前未知的锌结合位点，该位点对 ADAR1 的编辑活性很重要。此外，我们还提供了结构模型，解释了该酶的已知特性，并对独特存在于 ADAR1 中的表面环中特定残基的作用做出了预测。
