5WHJ

Crystal structure of Fab fragment of anti-FcRn antibody DX-2507


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.15 Å
  • R-Value Free: 0.225 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.182 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Structural basis for pH-insensitive inhibition of immunoglobulin G recycling by an anti-neonatal Fc receptor antibody.

Kenniston, J.A.Taylor, B.M.Conley, G.P.Cosic, J.Kopacz, K.J.Lindberg, A.P.Comeau, S.R.Atkins, K.Bullen, J.TenHoor, C.Adelman, B.A.Sexton, D.J.Edwards, T.E.Nixon, A.E.

(2017) J Biol Chem 292: 17449-17460

  • DOI: https://doi.org/10.1074/jbc.M117.807396
  • Primary Citation of Related Structures:  
    5WHJ, 5WHK

  • PubMed Abstract: 

    The neonatal Fc receptor FcRn plays a critical role in the trafficking of IgGs across tissue barriers and in retaining high circulating concentrations of both IgG and albumin. Although generally beneficial from an immunological perspective in maintaining IgG populations, FcRn can contribute to the pathogenesis of autoimmune disorders when an abnormal immune response targets normal biological components. We previously described a monoclonal antibody (DX-2507) that binds to FcRn with high affinity at both neutral and acidic pH, prevents the simultaneous binding of IgG, and reduces circulating IgG levels in preclinical animal models. Here, we report a 2.5 Å resolution X-ray crystal structure of an FcRn-DX-2507 Fab complex, revealing a nearly complete overlap of the IgG-Fc binding site in FcRn by complementarity-determining regions in DX-2507. This overlap explains how DX-2507 blocks IgG binding to FcRn and thereby shortens IgG half-life by preventing IgGs from recycling back into circulation. Moreover, the complex structure explains how the DX-2507 interaction is pH-insensitive unlike normal Fc interactions and how serum albumin levels are unaffected by DX-2507 binding. These structural studies could inform antibody-based therapeutic approaches for limiting the effects of IgG-mediated autoimmune disease.


  • Organizational Affiliation

    From Shire, Lexington, Massachusetts 02421, jkenniston0@shire.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
DX-2507 Fab heavy chainA [auth H]219Homo sapiensMutation(s): 0 
UniProt
Find proteins for S6BAN1 (Homo sapiens)
Explore S6BAN1 
Go to UniProtKB:  S6BAN1
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupS6BAN1
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
DX-2507 Fab light chainB [auth L]216Homo sapiensMutation(s): 0 
UniProt
Find proteins for Q6NS95 (Homo sapiens)
Explore Q6NS95 
Go to UniProtKB:  Q6NS95
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ6NS95
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.15 Å
  • R-Value Free: 0.225 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.182 
  • Space Group: P 43 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 116.17α = 90
b = 116.17β = 90
c = 79.22γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XSCALEdata scaling
PHASERphasing
PDB_EXTRACTdata extraction
XDSdata reduction

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-09-06
    Type: Initial release
  • Version 1.1: 2018-03-21
    Changes: Database references
  • Version 1.2: 2023-10-04
    Changes: Data collection, Database references, Refinement description