9kjs

The mTREX1-NSC 37215 complex structure by co-crystallization (NSC 37215-2 Complex 3)

spinqualitylabelsall models 9kjs, resolution 1.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9kjs is a 2 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.7Å Ligands: A1L50, FMT, MG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function TREX1_MOUSE Exonuclease with a preference for double stranded DNA with mismatched 3' termini. May play a role in DNA repair. Publication Abstract from PubMed 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 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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