2IQA

PFA2 FAB fragment, monoclinic apo form


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.279 
  • R-Value Work: 0.230 
  • R-Value Observed: 0.232 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Molecular basis for passive immunotherapy of Alzheimer's disease

Gardberg, A.S.Dice, L.T.Ou, S.Rich, R.L.Helmbrecht, E.Ko, J.Wetzel, R.Myszka, D.G.Patterson, P.H.Dealwis, C.

(2007) Proc Natl Acad Sci U S A 104: 15659-15664

  • DOI: https://doi.org/10.1073/pnas.0705888104
  • Primary Citation of Related Structures:  
    2IPT, 2IPU, 2IQ9, 2IQA, 2R0W, 2R0Z

  • PubMed Abstract: 

    Amyloid aggregates of the amyloid-beta (Abeta) peptide are implicated in the pathology of Alzheimer's disease. Anti-Abeta monoclonal antibodies (mAbs) have been shown to reduce amyloid plaques in vitro and in animal studies. Consequently, passive immunization is being considered for treating Alzheimer's, and anti-Abeta mAbs are now in phase II trials. We report the isolation of two mAbs (PFA1 and PFA2) that recognize Abeta monomers, protofibrils, and fibrils and the structures of their antigen binding fragments (Fabs) in complex with the Abeta(1-8) peptide DAEFRHDS. The immunodominant EFRHD sequence forms salt bridges, hydrogen bonds, and hydrophobic contacts, including interactions with a striking WWDDD motif of the antigen binding fragments. We also show that a similar sequence (AKFRHD) derived from the human protein GRIP1 is able to cross-react with both PFA1 and PFA2 and, when cocrystallized with PFA1, binds in an identical conformation to Abeta(1-8). Because such cross-reactivity has implications for potential side effects of immunotherapy, our structures provide a template for designing derivative mAbs that target Abeta with improved specificity and higher affinity.


  • Organizational Affiliation

    Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, TN 37996, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
IgG2a Fab fragment PFA2 Kappa light chainA [auth L],
C [auth A]
219Mus musculusMutation(s): 0 
UniProt
Find proteins for A2NHM3 (Mus musculus)
Explore A2NHM3 
Go to UniProtKB:  A2NHM3
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupA2NHM3
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
IgG2a Fab fragment PFA2 heavy chainB [auth H],
D [auth B]
223Mus musculusMutation(s): 0 
UniProt
Find proteins for Q811U5 (Mus musculus)
Explore Q811U5 
Go to UniProtKB:  Q811U5
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ811U5
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
GOL
Query on GOL

Download Ideal Coordinates CCD File 
F [auth L]
G [auth L]
I [auth H]
J [auth H]
L [auth A]
F [auth L],
G [auth L],
I [auth H],
J [auth H],
L [auth A],
M [auth A],
N [auth B],
O [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ACM
Query on ACM

Download Ideal Coordinates CCD File 
E [auth L],
K [auth A]
ACETAMIDE
C2 H5 N O
DLFVBJFMPXGRIB-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
H
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.279 
  • R-Value Work: 0.230 
  • R-Value Observed: 0.232 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 77.984α = 90
b = 73.412β = 99.97
c = 93.508γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
PDB_EXTRACTdata extraction
BIO-CARSdata collection
HKL-2000data reduction
SCALEPACKdata scaling
MOLREPphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2007-10-09
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Derived calculations, Version format compliance
  • Version 1.2: 2023-08-30
    Changes: Data collection, Database references, Derived calculations, Refinement description