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PDBsum entry 5o3y
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Oxidoreductase
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PDB id
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5o3y
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References listed in PDB file
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Key reference
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Title
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The cysteine-Reactive small molecule ebselen facilitates effective sod1 maturation.
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Authors
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M.J.Capper,
G.S.A.Wright,
L.Barbieri,
E.Luchinat,
E.Mercatelli,
L.Mcalary,
J.J.Yerbury,
P.M.O'Neill,
S.V.Antonyuk,
L.Banci,
S.S.Hasnain.
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Ref.
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Nat Commun, 2018,
9,
1693.
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PubMed id
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Abstract
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Superoxide dismutase-1 (SOD1) mutants, including those with unaltered enzymatic
activity, are known to cause amyotrophic lateral sclerosis (ALS). Several
destabilizing factors contribute to pathogenicity including a reduced ability to
complete the normal maturation process which comprises folding, metal cofactor
acquisition, intra-subunit disulphide bond formation and dimerization. Immature
SOD1 forms toxic oligomers and characteristic large insoluble aggregates within
motor system cells. Here we report that the cysteine-reactive molecule ebselen
efficiently confers the SOD1 intra-subunit disulphide and directs correct SOD1
folding, depopulating the globally unfolded precursor associated with
aggregation and toxicity. Assisted formation of the unusual SOD1 cytosolic
disulphide bond could have potential therapeutic applications. In less reducing
environments, ebselen forms a selenylsulphide with Cys111 and restores the
monomer-dimer equilibrium of A4V SOD1 to wild-type. Ebselen is therefore a
potent bifunctional pharmacological chaperone for SOD1 that combines properties
of the SOD1 chaperone hCCS and the recently licenced antioxidant drug, edaravone.
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