Summary information and primary citation
- PDB-id
-
7l35;
DSSR-derived features in text and
JSON formats; DNAproDB
- Class
- ligase-DNA
- Method
- X-ray (2.0 Å)
- Summary
- Human DNA ligase 1 - r771w nicked DNA complex
- Reference
-
Jurkiw TJ, Tumbale PP, Schellenberg MJ,
Cunningham-Rundles C, Williams RS, O'Brien PJ (2021):
"LIG1
syndrome mutations remodel a cooperative network of
ligand binding interactions to compromise ligation
efficiency." Nucleic Acids Res.,
49, 1619-1630. doi: 10.1093/nar/gkaa1297.
- 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.
