7L35

Human DNA Ligase 1 - R771W nicked DNA complex

7L35 の概要

• エントリーDOI: 10.2210/pdb7l35/pdb
• 分子名称: DNA ligase 1, DNA (5'-D(*GP*CP*TP*GP*AP*TP*GP*CP*GP*TP*C)-3'), DNA (5'-D(P*GP*TP*CP*GP*GP*AP*C)-3'), ... (9 entities in total)
• 機能のキーワード: dna ligase, ligase, ligase-dna complex, ligase/dna
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 83645.91

構造登録者

Tumbale, P.P.,Williams, R.S.,Schellenberg, M.S. (登録日: 2020-12-17, 公開日: 2021-01-13, 最終更新日: 2023-10-18)

主引用文献

Jurkiw, T.J.,Tumbale, P.P.,Schellenberg, M.J.,Cunningham-Rundles, C.,Williams, R.S.,O'Brien, P.J.
LIG1 syndrome mutations remodel a cooperative network of ligand binding interactions to compromise ligation efficiency.
Nucleic Acids Res., 49:1619-1630, 2021

PubMed Abstract: Human DNA ligase I (LIG1) is the main replicative ligase and it also seals DNA breaks to complete DNA repair and recombination pathways. Immune compromised patients harbor hypomorphic LIG1 alleles encoding substitutions of conserved arginine residues, R771W and R641L, that compromise LIG1 activity through poorly defined mechanisms. To understand the molecular basis of LIG1 syndrome mutations, we determined high resolution X-ray structures and performed systematic biochemical characterization of LIG1 mutants using steady-state and pre-steady state kinetic approaches. Our results unveil a cooperative network of plastic DNA-LIG1 interactions that connect DNA substrate engagement with productive binding of Mg2+ cofactors for catalysis. LIG1 syndrome mutations destabilize this network, compromising Mg2+ binding affinity, decreasing ligation efficiency, and leading to elevated abortive ligation that may underlie the disease pathology. These findings provide novel insights into the fundamental mechanism by which DNA ligases engage with a nicked DNA substrate, and they suggest that disease pathology of LIG1 syndrome could be modulated by Mg2+ levels.

PubMed: 33444456
DOI: 10.1093/nar/gkaa1297

実験手法

X-RAY DIFFRACTION (2 Å)