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Ligand binding and aggregation of pathogenic SOD1

DOI: 10.1038/ncomms2750 DOI Help

Authors: Gareth Wright (University of Liverpool) , Svetlana Antonyuk (University of Liverpool) , Neil Kershaw (University of Liverpool) , Richard Strange (University of Liverpool) , Samar Hasnain (University of Liverpool)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 4

State: Published (Approved)
Published: April 2013
Diamond Proposal Number(s): 2370

Open Access Open Access

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, ?-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.

Journal Keywords: Biological Sciences; Biochemistry; Neuroscience

Subject Areas: Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography

Other Facilities: Soleil