9nys

Human DNA Ligase 1 E346A/E592A/K845N triple mutant with 3'-A:T nick

spinqualitylabelsall models 9nys, resolution 2.64Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9nys is a 4 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.64Å Ligands: AMP, DMS Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function DNLI1_HUMAN DNA ligase that seals nicks in double-stranded DNA during DNA replication, DNA recombination and DNA repair. Publication Abstract from PubMed DNA ligase 1 (LIG1) joins broken strand breaks and seals Okazaki fragments during DNA repair and replication. Huntington's disease (HD)-associated mutation in the LIG1 gene, K845N, is associated with delayed symptom onset and predicted to suppress CAG repeat expansion. Yet, how this mutation impacts faithful nick sealing and efficient DNA binding by LIG1 remains unknown. Here, using biochemical analyses, X-ray crystallography, and total internal reflection fluorescence (TIRF) microscopy, we characterized the LIG1 HD-associated K845N variant at biochemical, structural, and single-molecule levels. Our results showed significantly reduced ligation efficiency for nick substrates containing noncanonical mismatches and diminished mutagenic end-joining of damaged DNA, while LIG1 K845N variant exhibits a lack of discrimination against nicks containing 3'-ribonucleotides when compared with the wild-type enzyme. Furthermore, our structures provided an atomic insight into differences in the distances between functional groups of K/N845 and DNA ends, demonstrating similar conformation at the ligase active site. Finally, our single-molecule measurements revealed that the K845N variant binds less frequently to nick, suggesting diminished affinity. Overall, our findings contribute to understanding the mechanism by which LIG1 searches for nick sites on DNA and ensures fidelity to maintain genome stability at the final ligation step in normal versus HD-associated states. Impaired nick recognition and ligation efficiency by LIG1 K845N variant linked to Huntington's disease.,Ratcliffe J, Lerner CE, Balu K, Chatterjee S, Lee KM, Caglayan M NAR Mol Med. 2025 Oct 28;2(4):ugaf038. doi: 10.1093/narmme/ugaf038. eCollection , 2025 Oct. PMID:41346861 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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