Structural discovery of small molecule binding sites in cu-Zn human superoxide dismutase familial amyotrophic lateral sclerosis mutants provides insights for lead optimization.
Dominant inheritance of point mutations in CuZn superoxide dismutase (SOD1) is
the best characterized subset of familial amyotrophic lateral sclerosis (FALS)
and accounts for some 20% of the known familial cases. We report the discovery
and visualization via cocrystallography of two ligand-binding pockets in human
SOD1 and its pathogenic mutants that have opened up the real possibility of
undertaking lead compound discovery using a fragment-based approach for
therapeutic purposes for SOD1 associated motor neuron disease.
