RCSB PDB - 6Z4L: A4V mutant of human SOD1 bound with 2-(pyridin-3-ylmethyl)benzoisoselenazolone derivative 9 in P21 space group

 6Z4L

A4V mutant of human SOD1 bound with 2-(pyridin-3-ylmethyl)benzoisoselenazolone derivative 9 in P21 space group


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.208 
  • R-Value Work: 0.182 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted Q8HClick on this verticalbar to view details

This is version 1.2 of the entry. See complete history


Literature

Novel Selenium-based compounds with therapeutic potential for SOD1-linked amyotrophic lateral sclerosis.

Amporndanai, K.Rogers, M.Watanabe, S.Yamanaka, K.O'Neill, P.M.Hasnain, S.S.

(2020) EBioMedicine 59: 102980-102980

  • DOI: https://doi.org/10.1016/j.ebiom.2020.102980
  • Primary Citation of Related Structures:  
    6Z3V, 6Z4G, 6Z4H, 6Z4I, 6Z4J, 6Z4K, 6Z4L, 6Z4M, 6Z4O

  • PubMed Abstract: 

    Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease as well as Lou Gehrig's disease, is a progressive neurological disorder selectively affecting motor neurons with no currently known cure. Around 20% of the familial ALS cases arise from dominant mutations in the sod1 gene encoding superoxide dismutase1 (SOD1) enzyme. Aggregation of mutant SOD1 in familial cases and of wild-type SOD1 in at least some sporadic ALS cases is one of the known causes of the disease. Riluzole, approved in 1995 and edaravone in 2017 remain the only drugs with limited therapeutic benefits. We have utilised the ebselen template to develop novel compounds that redeem stability of mutant SOD1 dimer and prevent aggregation. Binding modes of compounds have been visualised by crystallography. In vitro neuroprotection and toxicity of lead compounds have been performed in mouse neuronal cells and disease onset delay of ebselen has been demonstrated in transgenic ALS mice model. We have developed a number of ebselen-based compounds with improvements in A4V SOD1 stabilisation and in vitro therapeutic effects with significantly better potency than edaravone. Structure-activity relationship of hits has been guided by high resolution structures of ligand-bound A4V SOD1. We also show clear disease onset delay of ebselen in transgenic ALS mice model holding encouraging promise for potential therapeutic compounds. Our finding established the new generation of organo-selenium compounds with better in vitro neuroprotective activity than edaravone. The potential of this class of compounds may offer an alternative therapeutic agent for ALS treatment. The ability of these compounds to target cysteine 111 in SOD may have wider therapeutic applications targeting cysteines of enzymes involved in pathogenic and viral diseases including main protease of SARS-Cov-2 (COVID-19). Project funding was supported by the ALS Association grant (WA1128) and Fostering Joint International Research (19KK0214) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan.


  • Organizational Affiliation

    Molecular Biophysics Group, Department of Biochemistry and System Biology, Institute of System, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, L69 7ZB, United Kingdom.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Superoxide dismutase [Cu-Zn]A [auth AAA],
B [auth BBB]
153Homo sapiensMutation(s): 1 
Gene Names: SOD1
EC: 1.15.1.1
UniProt & NIH Common Fund Data Resources
Find proteins for P00441 (Homo sapiens)
Explore P00441 
Go to UniProtKB:  P00441
PHAROS:  P00441
GTEx:  ENSG00000142168 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00441
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
Q8H (Subject of Investigation/LOI)
Query on Q8H

Download Ideal Coordinates CCD File 
C [auth AAA],
H [auth BBB]
~{N}-(pyridin-3-ylmethyl)-2-selanyl-benzamide
C13 H12 N2 O Se
JMKKHOHSFFBFIN-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
F [auth AAA],
G [auth AAA],
K [auth BBB]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
ZN
Query on ZN

Download Ideal Coordinates CCD File 
D [auth AAA],
E [auth AAA],
I [auth BBB],
J [auth BBB]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.208 
  • R-Value Work: 0.182 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 38.93α = 90
b = 67.49β = 106.12
c = 50.78γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
DIALSdata reduction
Aimlessdata scaling
MOLREPphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted Q8HClick on this verticalbar to view details

Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Other privateUnited StatesWA1128

Revision History  (Full details and data files)

  • Version 1.0: 2020-09-16
    Type: Initial release
  • Version 1.1: 2024-01-24
    Changes: Data collection, Database references, Derived calculations, Refinement description
  • Version 1.2: 2024-11-13
    Changes: Structure summary