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Crystal structure of Tudor domain of TDRD3 in complex with a small molecule antagonist
Meixia Chen1, Zhuowen Wang1, Weiguo Li2
1Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Soochow University, Suzhou, Jiangsu 215123, PR China.
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.
Insights
Researchers developed a novel TDRD3 antagonist, Compound 2, by modifying an existing SMN antagonist. This triple-ring analog effectively binds to TDRD3, offering a new therapeutic strategy for related diseases.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Molecular Biology
Background:
- Tudor domain-containing protein 3 (TDRD3) plays a role in transcription, translation, breast cancer, neurodevelopment, and mental health.
- Targeting the TDRD3 Tudor domain with chemical probes is a promising therapeutic strategy.
- Previous work developed Compound 1 as an SMN antagonist.
Purpose of the Study:
- To develop and characterize a TDRD3 antagonist.
- To explore structural modifications for improved binding affinity.
- To provide a basis for developing antagonists for TDRD3 and SMN.
Main Methods:
- Synthesis of Compound 2, a triple-ring analog of Compound 1.
- Binding assays to assess TDRD3 interaction with Compound 2.
- Structural analysis to understand binding interactions.
- Structure-activity relationship studies for optimizing binding.
Main Results:
- TDRD3 effectively binds to Compound 2.
- Structural analysis revealed Compound 2 binds better to TDRD3 than Compound 1 to SMN, attributed to a smaller side chain.
- Adding a small hydrophobic group to Compound 1's N-methyl site enhanced binding.
Conclusions:
- Compound 2 is a potent TDRD3 antagonist.
- Structural insights guide the design of selective Tudor domain inhibitors.
- This research offers a pathway for developing antagonists for TDRD3 and SMN.
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