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PDBsum entry 6spk
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Oxidoreductase
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PDB id
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6spk
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PDB id:
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| Name: |
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Oxidoreductase
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Title:
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A4v mutant of human sod1 with ebselen derivative 6
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Structure:
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Superoxide dismutase [cu-zn]. Chain: a, b, e, f, i, j. Synonym: superoxide dismutase 1,hsod1. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: sod1. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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2.77Å
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R-factor:
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0.213
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R-free:
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0.229
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Authors:
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V.Chantadul,K.Amporndanai,G.Wright,M.Shahid,S.Antonyuk,S.Hasnain
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Key ref:
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V.Chantadul
et al.
(2020).
Ebselen as template for stabilization of A4V mutant dimer for motor neuron disease therapy.
Commun Biol,
3,
97.
PubMed id:
DOI:
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Date:
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01-Sep-19
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Release date:
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18-Mar-20
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PROCHECK
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Headers
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References
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P00441
(SODC_HUMAN) -
Superoxide dismutase [Cu-Zn] from Homo sapiens
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Seq:
Struc:
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154 a.a.
153 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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*
PDB and UniProt seqs differ
at 1 residue position (black
cross)
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Enzyme class:
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E.C.1.15.1.1
- superoxide dismutase.
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Reaction:
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2 superoxide + 2 H+ = H2O2 + O2
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2
×
superoxide
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+
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2
×
H(+)
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=
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H2O2
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+
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O2
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Cofactor:
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Fe cation or Mn(2+) or (Zn(2+) and Cu cation)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Commun Biol
3:97
(2020)
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PubMed id:
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Ebselen as template for stabilization of A4V mutant dimer for motor neuron disease therapy.
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V.Chantadul,
G.S.A.Wright,
K.Amporndanai,
M.Shahid,
S.V.Antonyuk,
G.Washbourn,
M.Rogers,
N.Roberts,
M.Pye,
P.M.O'Neill,
S.S.Hasnain.
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ABSTRACT
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Mutations to the gene encoding superoxide dismutase-1 (SOD1) were the first
genetic elements discovered that cause motor neuron disease (MND). These
mutations result in compromised SOD1 dimer stability, with one of the severest
and most common mutations Ala4Val (A4V) displaying a propensity to monomerise
and aggregate leading to neuronal death. We show that the clinically used
ebselen and related analogues promote thermal stability of A4V SOD1 when
binding to Cys111 only. We have developed a A4V SOD1 differential scanning
fluorescence-based assay on a C6S mutation background that is effective in
assessing suitability of compounds. Crystallographic data show that the selenium
atom of these compounds binds covalently to A4V SOD1 at Cys111 at the dimer
interface, resulting in stabilisation. This together with chemical amenability
for hit expansion of ebselen and its on-target SOD1 pharmacological chaperone
activity holds remarkable promise for structure-based therapeutics for MND using
ebselen as a template.
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Links
