7NTN
The structure of RRM domain of human TRMT2A at 2 A resolution
Summary for 7NTN
| Entry DOI | 10.2210/pdb7ntn/pdb |
| Descriptor | tRNA (uracil-5-)-methyltransferase homolog A, SULFATE ION, CHLORIDE ION, ... (5 entities in total) |
| Functional Keywords | trna binding, methyltransferase, trmt2a, polyq aggregation, transferase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 9727.40 |
| Authors | Davydova, E.,Janowski, R.,Witzenberger, M.,Niessing, D. (deposition date: 2021-03-10, release date: 2022-01-19, Last modification date: 2024-06-19) |
| Primary citation | 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 Cited by 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: 35070167DOI: 10.1016/j.csbj.2021.12.029 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.016 Å) |
Structure validation
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