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)