Disordered DNA-binding motif forms a modulation site for inhibiting the cancer immunotherapy target TREX1.
Journal
Nucleic acids research
Journal Volume
54
Journal Issue
2
Start Page
gkaf1511
ISSN
1362-4962
Date Issued
2026-01-14
Author(s)
Huang, Kuan-Wei
Yu Tsai, Chieh-
Wu, Chia-Yun
Lin, Wei-Cheng
Wu, Meng-Tzu
Hsu, Kai-Cheng
Yu Yang, Chen-
Chang, I-Ya
Chu, Jhih-Wei
Hsiao, Yu-Yuan
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.
Type
journal article