9HGM
Structure of human DNMT2 with bound allosteric inhibitor
This is a non-PDB format compatible entry.
Summary for 9HGM
| Entry DOI | 10.2210/pdb9hgm/pdb |
| Descriptor | tRNA (cytosine(38)-C(5))-methyltransferase, 4-ethyl-~{N}-[[1-[[(2~{R})-1-(1~{H}-indol-3-yl)-4-[[2-(methylamino)-2-oxidanylidene-ethyl]amino]-4-oxidanylidene-butan-2-yl]carbamoyl]cyclopropyl]methyl]benzamide, GLYCEROL, ... (4 entities in total) |
| Functional Keywords | methyl transferase, trna methylation, allosteric inhibitor, drug design, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 80755.20 |
| Authors | Schwan, M.,Kopp, J.,Sinning, I. (deposition date: 2024-11-20, release date: 2025-08-27, Last modification date: 2025-09-10) |
| Primary citation | Frey, A.F.,Schwan, M.,Weldert, A.C.,Kadenbach, V.,Kopp, J.,Nidoieva, Z.,Zimmermann, R.A.,Gleue, L.,Zimmer, C.,Jorg, M.,Friedland, K.,Helm, M.,Sinning, I.,Barthels, F. DNA-encoded library screening uncovers potent DNMT2 inhibitors targeting a cryptic allosteric binding site. Iscience, 28:113300-113300, 2025 Cited by PubMed Abstract: DNMT2 (TRDMT1) is a human RNA methyltransferase implicated in various disease processes. However, small-molecule targeting of DNMT2 remains challenging due to poor selectivity and low cellular availability of known -adenosylhomocysteine (SAH)-derived ligands. In this study, a DNA-encoded library (DEL) screen identified five non-SAH-like chemotypes that selectively bind DNMT2, including three peptidomimetics. Orthogonal assays confirmed target engagement, and X-ray crystallography revealed a previously unknown allosteric binding pocket formed via active site loop rearrangement. Guided by structural insights, the authors optimized a lead compound with a of 3.04 μM that reduces mC levels in MOLM-13 tRNA and synergizes with doxorubicin to impair cell viability. These inhibitors exhibit unprecedented selectivity over other methyltransferases, offering a promising scaffold for future DNMT2-targeting therapeutics. Beyond pharmacological implications, the study provides conceptual advances in understanding allosteric modulation and structural plasticity of DNMT2. PubMed: 40894903DOI: 10.1016/j.isci.2025.113300 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.6 Å) |
Structure validation
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