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The mTREX1-NSC 37203 complex structure by soaking in Soaking Condition 1 (NSC 37203 complex 2)
Structural highlights
FunctionTREX1_MOUSE Exonuclease with a preference for double stranded DNA with mismatched 3' termini. May play a role in DNA repair.[1] [2] Publication Abstract from PubMedIn 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 alpha7-alpha8 loop is discovered by X-ray crystallography with newly identified inhibitors. Despite that the structure of alpha7-alpha8 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 alpha7-alpha8 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. Disordered DNA-binding motif forms a modulation site for inhibiting the cancer immunotherapy target TREX1.,Huang KW, Yu Tsai C, Wu CY, Lin WC, Wu MT, Hsu KC, Yu Yang C, Chang IY, Liu HM, Chu JW, Hsiao YY Nucleic Acids Res. 2026 Jan 14;54(2):gkaf1511. doi: 10.1093/nar/gkaf1511. PMID:41533589[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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