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The cysteine-reactive small molecule ebselen facilitates effective SOD1 maturation
DOI:
10.1038/s41467-018-04114-x
Authors:
Michael J.
Capper
(University of Liverpool)
,
Gareth S. A.
Wright
(University of Liverpool)
,
Letizia
Barbieri
(University of Florence; Interuniversity Consortium for Magnetic Resonance of Metallo Proteins (CIRMMP))
,
Enrico
Luchinat
(University of Florence)
,
Eleonora
Mercatelli
(University of Florence)
,
Luke
Mcalary
(University of Wollongong)
,
Justin J.
Yerbury
(University of Wollongong)
,
Paul M.
O’neill
(University of Liverpool)
,
Svetlana V.
Antonyuk
(University of Liverpool)
,
Lucia
Banci
(University of Florence)
,
S. Samar
Hasnain
(University of Liverpool)
Co-authored by industrial partner:
No
Type:
Journal Paper
Journal:
Nature Communications
, VOL 9
State:
Published (Approved)
Published:
April 2018

Abstract: 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.
Journal Keywords: Drug discovery; Molecular conformation; X-ray crystallography
Diamond Keywords: Motor Neurone Disease
Subject Areas:
Biology and Bio-materials,
Medicine
Instruments:
I02-Macromolecular Crystallography
Other Facilities: SOLEIL
Added On:
09/05/2018 11:33
Documents:
s41467-018-04114-x.pdf
Discipline Tags:
Neurodegenerative Diseases
Non-Communicable Diseases
Health & Wellbeing
Neurology
Structural biology
Drug Discovery
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)