Ligand binding and aggregation of pathogenic SOD1.
Article Details
- CitationCopy to clipboard
Wright GS, Antonyuk SV, Kershaw NM, Strange RW, Samar Hasnain S
Ligand binding and aggregation of pathogenic SOD1.
Nat Commun. 2013;4:1758. doi: 10.1038/ncomms2750.
- PubMed ID
- 23612299 [ View in PubMed]
- Abstract
Mutations in the gene encoding Cu/Zn superoxide dismutase-1 cause amyotrophic lateral sclerosis. Superoxide dismutase-1 mutations decrease protein stability and promote aggregation. The mutant monomer is thought to be an intermediate in the pathway from the superoxide 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 reattainment of the monomer-dimer equilibrium. Intervention to stabilize the superoxide dismutase-1 dimer and inhibit aggregation is regarded as a potential therapeutic strategy. We describe protein-ligand interactions for two compounds, Isoproterenol and 5-fluorouridine, highlighted as superoxide dismutase-1 stabilizers. We find both compounds interact with superoxide dismutase-1 at a key region identified at the core of the superoxide dismutase-1 fibrillar aggregates, beta-barrel loop II-strand 3, rather than the proposed dimer interface site. This illustrates the need for direct structural observations when developing compounds for protein-targeted therapeutics.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions 5-fluorouridine Superoxide dismutase [Cu-Zn] Protein Humans UnknownNot Available Details Dopamine Superoxide dismutase [Cu-Zn] Protein Humans UnknownNot Available Details Isoprenaline Superoxide dismutase [Cu-Zn] Protein Humans UnknownStabilizationDetails