9KJD

The apo-mTREX1 crystal structure for soaking experiments (Soaking Condition 1)

Summary for 9KJD

• Entry DOI: 10.2210/pdb9kjd/pdb
• Descriptor: Three-prime repair exonuclease 1, ACETATE ION (3 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: 55248.57

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

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: 41533589
DOI: 10.1093/nar/gkaf1511

Experimental method

X-RAY DIFFRACTION (1.7 Å)