6FAX

Complex of Human CD40 Ectodomain with Lob 7.4 Fab

  • Classification: IMMUNE SYSTEM
  • Organism(s): Homo sapiens
  • Expression System: Homo sapiens
  • Mutation(s): No 

  • Deposited: 2017-12-18 Released: 2018-02-07 
  • Deposition Author(s): Orr, C.M., Tews, I., Pearson, A.R.
  • Funding Organization(s): German Research Foundation, German Federal Excellence Cluste, Institute for Life Sciences, University of Southampton, Antibody and Vaccine Group,, Cancer Research UK Antibody Programme, European Union

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.99 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.185 
  • R-Value Observed: 0.187 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Complex Interplay between Epitope Specificity and Isotype Dictates the Biological Activity of Anti-human CD40 Antibodies.

Yu, X.Chan, H.T.C.Orr, C.M.Dadas, O.Booth, S.G.Dahal, L.N.Penfold, C.A.O'Brien, L.Mockridge, C.I.French, R.R.Duriez, P.Douglas, L.R.Pearson, A.R.Cragg, M.S.Tews, I.Glennie, M.J.White, A.L.

(2018) Cancer Cell 33: 664-675.e4

  • DOI: https://doi.org/10.1016/j.ccell.2018.02.009
  • Primary Citation of Related Structures:  
    6FAX

  • PubMed Abstract: 

    Anti-CD40 monoclonal antibodies (mAbs) that promote or inhibit receptor function hold promise as therapeutics for cancer and autoimmunity. Rules governing their diverse range of functions, however, are lacking. Here we determined characteristics of nine hCD40 mAbs engaging epitopes throughout the CD40 extracellular region expressed as varying isotypes. All mAb formats were strong agonists when hyper-crosslinked; however, only those binding the membrane-distal cysteine-rich domain 1 (CRD1) retained agonistic activity with physiological Fc gamma receptor crosslinking or as human immunoglobulin G2 isotype; agonistic activity decreased as epitopes drew closer to the membrane. In addition, all CRD2-4 binding mAbs blocked CD40 ligand interaction and were potent antagonists. Thus, the membrane distal CRD1 provides a region of choice for selecting CD40 agonists while CRD2-4 provides antagonistic epitopes.


  • Organizational Affiliation

    Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton SO16 6YD, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Lob 7.4 light chainA [auth L]214Homo sapiensMutation(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
Lob 7.4 heavy chainB [auth H]240Homo sapiensMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Tumor necrosis factor receptor superfamily member 5C [auth R]173Homo sapiensMutation(s): 0 
Gene Names: CD40TNFRSF5
UniProt & NIH Common Fund Data Resources
Find proteins for P25942 (Homo sapiens)
Explore P25942 
Go to UniProtKB:  P25942
PHAROS:  P25942
GTEx:  ENSG00000101017 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP25942
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.99 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.185 
  • R-Value Observed: 0.187 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 158.753α = 90
b = 158.753β = 90
c = 93.622γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
xia2data reduction
Aimlessdata scaling
MOLREPphasing

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
German Research FoundationGermany--
German Federal Excellence ClusteGermany--
Institute for Life Sciences, University of SouthamptonUnited Kingdom--
Antibody and Vaccine Group,United Kingdom--
Cancer Research UK Antibody ProgrammeUnited Kingdom--
European Union602262-2

Revision History  (Full details and data files)

  • Version 1.0: 2018-02-07
    Type: Initial release
  • Version 1.1: 2018-04-04
    Changes: Data collection, Database references
  • Version 1.2: 2018-04-18
    Changes: Data collection, Database references
  • Version 1.3: 2024-01-17
    Changes: Data collection, Database references, Refinement description