Crystal structure of Tudor domain of TDRD3 in complex with a small molecule antagonist

IF 2.6 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et Biophysica Acta-Gene Regulatory Mechanisms Pub Date : 2023-09-01 DOI:10.1016/j.bbagrm.2023.194962

Meixia Chen , Zhuowen Wang , Weiguo Li , Yichang Chen , Qin Xiao , Xinci Shang , Xiaolei Huang , Zhengguo Wei , Xinyue Ji , Yanli Liu

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Abstract

Tudor domain-containing protein 3 (TDRD3) is involved in regulating transcription and translation, promoting breast cancer progression, and modulating neurodevelopment and mental health, making it a promising therapeutic target for associated diseases. The Tudor domain of TDRD3 is essential for its biological functions, and targeting this domain with potent and selective chemical probes may modulate its engagement with chromatin and related functions. Here we reported a study of TDRD3 antagonist following on our earlier work on the development of the SMN antagonist, Compound 1, and demonstrated that TDRD3 can bind effectively to Compound 2, a triple-ring analog of Compound 1. Our structural analysis suggested that the triple-ring compound bound better to TDRD3 due to its smaller side chain at Y566 compared to W102 in SMN. We also revealed that adding a small hydrophobic group to the N-methyl site of Compound 1 can improve binding. These findings provide a path for identifying antagonists for single canonical Tudor domain-containing proteins such as TDRD3 and SMN.

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TDRD3与小分子拮抗剂配合物都铎结构域的晶体结构

都铎结构域蛋白3（TDRD3）参与调节转录和翻译，促进乳腺癌症进展，调节神经发育和心理健康，使其成为相关疾病的一个有前途的治疗靶点。TDRD3的都铎结构域对其生物学功能至关重要，用有效和选择性的化学探针靶向该结构域可能调节其与染色质的结合和相关功能。在此，我们报道了继我们早期开发SMN拮抗剂化合物1的工作之后对TDRD3拮抗剂的研究，并证明TDRD3可以有效地与化合物2结合，化合物2是化合物1的三环类似物。我们的结构分析表明，与SMN中的W102相比，三环化合物在Y566处的侧链较小，因此与TDRD3结合得更好。我们还揭示了在化合物1的N-甲基位点添加小的疏水基团可以改善结合。这些发现为鉴定含有TDRD3和SMN等单一典型都铎结构域的蛋白质的拮抗剂提供了途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biochimica et Biophysica Acta-Gene Regulatory Mechanisms 生物-生化与分子生物学

CiteScore

9.20

自引率

2.10%

发文量

审稿时长

44 days

期刊介绍： BBA Gene Regulatory Mechanisms includes reports that describe novel insights into mechanisms of transcriptional, post-transcriptional and translational gene regulation. Special emphasis is placed on papers that identify epigenetic mechanisms of gene regulation, including chromatin, modification, and remodeling. This section also encompasses mechanistic studies of regulatory proteins and protein complexes; regulatory or mechanistic aspects of RNA processing; regulation of expression by small RNAs; genomic analysis of gene expression patterns; and modeling of gene regulatory pathways. Papers describing gene promoters, enhancers, silencers or other regulatory DNA regions must incorporate significant functions studies.