Disordered DNA-binding motif forms a modulation site for inhibiting the cancer immunotherapy target TREX1.

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 c

SUBMITTER: Huang KW 

PROVIDER: S-EPMC12802895 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature