Disordered DNA-binding motif forms a modulation site for inhibiting the cancer immunotherapy target TREX1
Year: 2025
Type: article
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.
Source: Nucleic Acids Research
DOI: 10.1093/nar/gkaf1511
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,992
Awards: Molecular Mechanisms of Multifunctional Enzyme Activity and Drug Development in Emerging Cancer Therapeutic Target Ape1., G2438053898, G3529738027, G5025714613, G6324842879, Combined Physics-Based Simulation and Ai-Driven Computation for Smart Experimentation on the Structural Dynamics and Inhibitor Discovery of Intrinsically Disordered Proteins( I ), Dissection of Chemomechanical Diversity in Biomolecular Structural Homology, Combined Physics-Based Simulation and Ai-Driven Computation for Smart Experimentation on the Structural Dynamics and Inhibitor Discovery of Intrinsically Disordered Proteins( II )
OpenAlex ID: W7124247787