7NTN

The structure of RRM domain of human TRMT2A at 2 A resolution

7NTN の概要

• エントリーDOI: 10.2210/pdb7ntn/pdb
• 分子名称: tRNA (uracil-5-)-methyltransferase homolog A, SULFATE ION, CHLORIDE ION, ... (5 entities in total)
• 機能のキーワード: trna binding, methyltransferase, trmt2a, polyq aggregation, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 9727.40

構造登録者

Davydova, E.,Janowski, R.,Witzenberger, M.,Niessing, D. (登録日: 2021-03-10, 公開日: 2022-01-19, 最終更新日: 2024-06-19)

主引用文献

Margreiter, M.A.,Witzenberger, M.,Wasser, Y.,Davydova, E.,Janowski, R.,Metz, J.,Habib, P.,Sahnoun, S.E.M.,Sobisch, C.,Poma, B.,Palomino-Hernandez, O.,Wagner, M.,Carell, T.,Jon Shah, N.,Schulz, J.B.,Niessing, D.,Voigt, A.,Rossetti, G.
Small-molecule modulators of TRMT2A decrease PolyQ aggregation and PolyQ-induced cell death.
Comput Struct Biotechnol J, 20:443-458, 2022

PubMed Abstract: Polyglutamine (polyQ) diseases are characterized by an expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats encoding for an uninterrupted prolonged polyQ tract. We previously identified TRMT2A as a strong modifier of polyQ-induced toxicity in an unbiased large-scale screen in . This work aimed at identifying and validating pharmacological TRMT2A inhibitors as treatment opportunities for polyQ diseases in humans. Computer-aided drug discovery was implemented to identify human TRMT2A inhibitors. Additionally, the crystal structure of one protein domain, the RNA recognition motif (RRM), was determined, and Biacore experiments with the RRM were performed. The identified molecules were validated for their potency to reduce polyQ aggregation and polyQ-induced cell death in human HEK293T cells and patient derived fibroblasts. Our work provides a first step towards pharmacological inhibition of this enzyme and indicates TRMT2A as a viable drug target for polyQ diseases.

PubMed: 35070167
DOI: 10.1016/j.csbj.2021.12.029

実験手法

X-RAY DIFFRACTION (2.016 Å)