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.
Antonyuk
Svetlana
S
Molecular Biophysics Group, School of Biological Sciences, University of Liverpool, Liverpool L69 7ZB, UK.
Strange
Richard W
RW
Hasnain
S Samar
SS
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D008956:Models, Chemical; D009154:Mutation / Q000235:genetics*; D054852:Small Molecule Libraries; D013482:Superoxide Dismutase / Q000737:chemistry*
D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D013482:Superoxide Dismutase