6UG8

Complex of ch28/11 Fab and SSEA-4 (monoclinic form)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.89 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.179 

wwPDB Validation   3D Report Full Report

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This is version 2.1 of the entry. See complete history


Literature

The terminal sialic acid of stage-specific embryonic antigen-4 has a crucial role in binding to a cancer-targeting antibody.

Soliman, C.Chua, J.X.Vankemmelbeke, M.McIntosh, R.S.Guy, A.J.Spendlove, I.Durrant, L.G.Ramsland, P.A.

(2020) J Biol Chem 295: 1009-1020

  • DOI: https://doi.org/10.1074/jbc.RA119.011518
  • Primary Citation of Related Structures:  
    6UG7, 6UG8, 6UG9, 6UGA

  • PubMed Abstract: 

    Cancer remains a leading cause of morbidity and mortality worldwide, requiring ongoing development of targeted therapeutics such as monoclonal antibodies. Carbohydrates on embryonic cells are often highly expressed in cancer and are therefore attractive targets for antibodies. Stage-specific embryonic antigen-4 (SSEA-4) is one such glycolipid target expressed in many cancers, including breast and ovarian carcinomas. Here, we defined the structural basis for recognition of SSEA-4 by a novel monospecific chimeric antibody (ch28/11). Five X-ray structures of ch28/11 Fab complexes with the SSEA-4 glycan headgroup, determined at 1.5-2.7 Å resolutions, displayed highly similar three-dimensional structures indicating a stable binding mode. The structures also revealed that by adopting a horseshoe-shaped conformation in a deep groove, the glycan headgroup likely sits flat against the membrane to allow the antibody to interact with SSEA-4 on cancer cells. Moreover, we found that the terminal sialic acid of SSEA-4 plays a dominant role in dictating the exquisite specificity of the ch28/11 antibody. This observation was further supported by molecular dynamics simulations of the ch28/11-glycan complex, which show that SSEA-4 is stabilized by its terminal sialic acid, unlike SSEA-3, which lacks this sialic acid modification. These high-resolution views of how a glycolipid interacts with an antibody may help to advance a new class of cancer-targeting immunotherapy.


  • Organizational Affiliation

    School of Science, RMIT University, Melbourne, Victoria 3083, Australia.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
ch28/11 Fab light chainA [auth L]213Mus musculusMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
ch28/11 Fab heavy chainB [auth H]218Mus musculusMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
Expand
  • Reference Sequence
Oligosaccharides

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Entity ID: 3
MoleculeChains Length2D Diagram Glycosylation3D Interactions
N-acetyl-alpha-neuraminic acid-(2-3)-beta-D-galactopyranose-(1-3)-2-acetamido-2-deoxy-beta-D-galactopyranose-(1-3)-alpha-D-galactopyranose-(1-4)-beta-D-galactopyranose-(1-4)-beta-D-glucopyranoseC [auth A]6N/A
Glycosylation Resources
GlyTouCan:  G32254QI
GlyCosmos:  G32254QI
GlyGen:  G32254QI
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.89 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.179 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 37.464α = 90
b = 69.167β = 94.46
c = 97.55γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
XSCALEdata scaling
PHENIXphasing

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-12-18
    Type: Initial release
  • Version 1.1: 2020-01-01
    Changes: Database references
  • Version 1.2: 2020-02-05
    Changes: Data collection, Database references
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Advisory, Atomic model, Data collection, Derived calculations, Structure summary
  • Version 2.1: 2023-10-11
    Changes: Data collection, Database references, Derived calculations, Refinement description, Structure summary