Mutations in the gene encoding Cu/Zn superoxide dismutase-1 cause amyotrophic lateralsclerosis. Superoxide dismutase-1 mutations decrease protein stability and promote aggregation.The mutant monomer is thought to be an intermediate in the pathway from thesuperoxide dismutase-1 dimer to aggregate. Here we find that the monomeric copper-apo,zinc-holo protein is structurally perturbed and the apo-protein aggregates without reattainmentof the monomer–dimer equilibrium. Intervention to stabilize the superoxide dismutase-1dimer and inhibit aggregation is regarded as a potential therapeutic strategy. We describeprotein–ligand interactions for two compounds, isoproterenol and 5-fluorouridine, highlightedas superoxide dismutase-1 stabilizers. We find both compounds interact with superoxidedismutase-1 at a key region identified at the core of the superoxide dismutase-1 fibrillaraggregates, b-barrel loop II–strand 3, rather than the proposed dimer interface site.This illustrates the need for direct structural observations when developing compounds forprotein-targeted therapeutics.
展开▼
