9KJS
The mTREX1-NSC 37215 complex structure by co-crystallization (NSC 37215-2 Complex 3)
This is a non-PDB format compatible entry.
Summary for 9KJS
| Entry DOI | 10.2210/pdb9kjs/pdb |
| Related | 9KJD 9KJE 9KJF 9KJG 9KJH 9KJI 9KJJ 9KJK 9KJL 9KJM 9KJN 9KJO 9KJP 9KJQ |
| Descriptor | Three-prime repair exonuclease 1, 7-[(4-benzamidophenyl)carbonylamino]-4-oxidanyl-naphthalene-2-sulfonic acid, MAGNESIUM ION, ... (5 entities in total) |
| Functional Keywords | trex1, inhibitor, deddh exonuclease, hydrolase |
| Biological source | Mus musculus (house mouse) |
| Total number of polymer chains | 2 |
| Total formula weight | 55427.11 |
| Authors | Hsiao, Y.Y.,Huang, K.W.,Wu, C.Y.,Tsai, C.Y.,Wu, M.T. (deposition date: 2024-11-12, release date: 2026-01-28) |
| Primary citation | Huang, K.W.,Yu Tsai, C.,Wu, C.Y.,Lin, W.C.,Wu, M.T.,Hsu, K.C.,Yu Yang, C.,Chang, I.Y.,Liu, H.M.,Chu, J.W.,Hsiao, Y.Y. Disordered DNA-binding motif forms a modulation site for inhibiting the cancer immunotherapy target TREX1. Nucleic Acids Res., 54:-, 2026 Cited by PubMed Abstract: In nucleic acid-binding proteins, short linear motifs (SLiMs)-an important subclass of intrinsically disordered regions (IDRs)-offer diverse opportunities for therapeutic intervention, yet their structural and functional roles remain largely elusive. Away from the active site of cancer immunotherapy target exonuclease TREX1, a novel modulation site formed by the intrinsically disordered α7-α8 loop is discovered by X-ray crystallography with newly identified inhibitors. Despite that the structure of α7-α8 loop upon binding-coupled disordered-to-ordered transition is inhibitor specific, a pattern of multivertex clamping is consistently observed. Mechanistically, the fuzzy TREX1-inhibitor interactions elucidated by structural analysis and molecular dynamics simulations reveal an ensemble of chemical-scale amphiphilic units for inhibitor moieties to anchor to. Functional assays confirm that our newly identified inhibitors disrupt the DNA binding and immunosuppressive activity of TREX1, establishing α7-α8 loop as a druggable SLiM. This work provides a first collection of atomic details for small-molecule inhibition involving a DNA-binding SLiM, and the mechanistic principles uncovered here may be generalized to targeting IDRs in cancer immunotherapy. PubMed: 41533589DOI: 10.1093/nar/gkaf1511 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.7 Å) |
Structure validation
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