4IJ3

Oxidoreductase Fragment of Human QSOX1 in Complex with a FAB Fragment from an Anti- Human QSOX1 Antibody


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.237 
  • R-Value Work: 0.202 

wwPDB Validation   3D Report Full Report


This is version 2.1 of the entry. See complete history


Literature

An Inhibitory Antibody Blocks the First Step in the Dithiol/Disulfide Relay Mechanism of the Enzyme QSOX1.

Grossman, I.Alon, A.Ilani, T.Fass, D.

(2013) J Mol Biol 425: 4366-4378

  • DOI: https://doi.org/10.1016/j.jmb.2013.07.011
  • Primary Citation of Related Structures:  
    4IJ3

  • PubMed Abstract: 

    Quiescin sulfhydryl oxidase 1 (QSOX1) is a catalyst of disulfide bond formation that undergoes regulated secretion from fibroblasts and is over-produced in adenocarcinomas and other cancers. We have recently shown that QSOX1 is required for incorporation of particular laminin isoforms into the extracellular matrix (ECM) of cultured fibroblasts and, as a consequence, for tumor cell adhesion to and penetration of the ECM. The known role of laminins in integrin-mediated cell survival and motility suggests that controlling QSOX1 activity may provide a novel means of combating metastatic disease. With this motivation, we developed a monoclonal antibody that inhibits the activity of human QSOX1. Here, we present the biochemical and structural characterization of this antibody and demonstrate that it is a tight-binding inhibitor that blocks one of the redox-active sites in the enzyme, but not the site at which de novo disulfides are generated catalytically. Sulfhydryl oxidase activity is thus prevented without direct binding of the sulfhydryl oxidase domain, confirming the model for the interdomain QSOX1 electron transfer mechanism originally surmised based on mutagenesis and protein dissection. In addition, we developed a single-chain variant of the antibody and show that it is a potent QSOX1 inhibitor. The QSOX1 inhibitory antibody will be a valuable tool in studying the role of ECM composition and architecture in cell migration, and the recombinant version may be further developed for potential therapeutic applications based on manipulation of the tumor microenvironment.


  • Organizational Affiliation

    Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100, Israel.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Sulfhydryl oxidase 1244Homo sapiensMutation(s): 0 
Gene Names: QSOX1QSCN6UNQ2520/PRO6013
EC: 1.8.3.2
UniProt & NIH Common Fund Data Resources
Find proteins for O00391 (Homo sapiens)
Explore O00391 
Go to UniProtKB:  O00391
PHAROS:  O00391
GTEx:  ENSG00000116260 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO00391
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Light chain of FAB fragment214Mus musculusMutation(s): 0 
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  • Reference Sequence
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Heavy chain of FAB fragment221Mus musculusMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.237 
  • R-Value Work: 0.202 
  • Space Group: P 61
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 209.311α = 90
b = 209.311β = 90
c = 55.265γ = 120
Software Package:
Software NamePurpose
StructureStudiodata collection
PHASERphasing
CNSrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-11-06
    Type: Initial release
  • Version 2.0: 2019-08-14
    Changes: Advisory, Data collection, Database references, Polymer sequence, Source and taxonomy, Structure summary
  • Version 2.1: 2023-11-08
    Changes: Data collection, Database references, Derived calculations, Refinement description