6BB4

Fab/epitope complex of mouse monoclonal antibody C5.2 targeting a phospho-tau epitope.

  • Classification: IMMUNE SYSTEM
  • Organism(s): Mus musculus, Homo sapiens
  • Mutation(s): No 

  • Deposited: 2017-10-16 Released: 2018-05-02 
  • Deposition Author(s): Chukwu, J.E., Kong, X.-P.
  • Funding Organization(s): National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS), National Institutes of Health/National Institute on Aging (NIH/NIA)

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.270 
  • R-Value Work: 0.218 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Tau Antibody Structure Reveals a Molecular Switch Defining a Pathological Conformation of the Tau Protein.

Chukwu, J.E.Pedersen, J.T.Pedersen, L.O.Volbracht, C.Sigurdsson, E.M.Kong, X.P.

(2018) Sci Rep 8: 6209-6209

  • DOI: https://doi.org/10.1038/s41598-018-24276-4
  • Primary Citation of Related Structures:  
    6BB4

  • PubMed Abstract: 

    Tau antibodies have shown therapeutic potential for Alzheimer's disease and several are in clinical trials. As a microtubule-associated protein, tau relies on dynamic phosphorylation for its normal functions. In tauopathies, it becomes hyperphosphorylated and aggregates into toxic assemblies, which collectively lead to neurodegeneration. Of the phospho-epitopes, the region around Ser396 has received particular attention because of its prominence and stability in tauopathies. Here we report the first structure of a monoclonal tau antibody in complex with the pathologically important phospho-Ser396 residue. Its binding region reveals tau residues Tyr394 to phospho-Ser396 stabilized in a β-strand conformation that is coordinated by a phospho-specific antigen binding site. These details highlight a molecular switch that defines this prominent conformation of tau and ways to target it. Overall, the structure of the antibody-antigen complex clarifies why certain phosphorylation sites in tau are more closely linked to neurodegeneration than others.


  • Organizational Affiliation

    Departments of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, NY, USA.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Mouse monoclonal antibody C5.2 Fab light chainA [auth L],
D [auth M],
G [auth N]
213Mus musculusMutation(s): 0 
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Mouse monoclonal antibody C5.2 Fab heavy chainB [auth H],
E [auth I],
H [auth J]
220Mus musculusMutation(s): 0 
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  • Reference Sequence

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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Microtubule-associated protein tauC [auth P],
F [auth Q],
I [auth R]
23Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for P10636 (Homo sapiens)
Explore P10636 
Go to UniProtKB:  P10636
PHAROS:  P10636
GTEx:  ENSG00000186868 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP10636
Sequence Annotations
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  • Reference Sequence
Small Molecules
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
SEP
Query on SEP
C [auth P],
F [auth Q],
I [auth R]
L-PEPTIDE LINKINGC3 H8 N O6 PSER
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.270 
  • R-Value Work: 0.218 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 161.156α = 90
b = 40.535β = 104.07
c = 228.064γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XDSdata scaling
PHASERphasing
Cootmodel building

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)United StatesNS077239
National Institutes of Health/National Institute on Aging (NIH/NIA)United StatesAG032611

Revision History  (Full details and data files)

  • Version 1.0: 2018-05-02
    Type: Initial release
  • Version 1.1: 2019-12-18
    Changes: Author supporting evidence