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PDBsum entry 2ipu

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protein ligands Protein-protein interface(s) links
Immune system PDB id
2ipu
Jmol
Contents
Protein chains
219 a.a. *
223 a.a. *
Ligands
ALA-GLU-PHE-ARG-
HIS-ASP-SER
×2
ACM ×3
GOL ×6
Waters ×118
* Residue conservation analysis
PDB id:
2ipu
Name: Immune system
Title: Pfa1 fab fragment complexed with abeta 1-8 peptide
Structure: Igg2a fab fragment heavy chain. Chain: l, k. Igg2a fab fragment light chain kappa. Chain: h, g. Abeta 1-8 peptide. Chain: p, q. Engineered: yes
Source: Mus musculus. House mouse. Organism_taxid: 10090. Strain: balb/c. Other_details: hybridoma. Synthetic: yes. Other_details: this sequence occurs naturally in homo sapie (humans)
Resolution:
1.65Å     R-factor:   0.184     R-free:   0.225
Authors: A.S.Gardberg,C.Dealwis
Key ref:
A.S.Gardberg et al. (2007). Molecular basis for passive immunotherapy of Alzheimer's disease. Proc Natl Acad Sci U S A, 104, 15659-15664. PubMed id: 17895381 DOI: 10.1073/pnas.0705888104
Date:
12-Oct-06     Release date:   09-Oct-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
A2NHM3  (A2NHM3_MOUSE) -  If kappa light chain (Fragment)
Seq:
Struc:
219 a.a.
219 a.a.*
Protein chains
No UniProt id for this chain
Struc: 223 a.a.
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 4 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     B cell differentiation   1 term 
  Biochemical function     metal ion binding     1 term  

 

 
DOI no: 10.1073/pnas.0705888104 Proc Natl Acad Sci U S A 104:15659-15664 (2007)
PubMed id: 17895381  
 
 
Molecular basis for passive immunotherapy of Alzheimer's disease.
A.S.Gardberg, L.T.Dice, S.Ou, R.L.Rich, E.Helmbrecht, J.Ko, R.Wetzel, D.G.Myszka, P.H.Patterson, C.Dealwis.
 
  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.
 
  Selected figure(s)  
 
Figure 2.
Fig. 2. PFA1 and PFA2 bind to the A (1–8) peptide. (a) Stereoview of a simulated-annealing omit map contoured at 3 shows the electron density for the free DAEFRHDS peptide bound to the CDR of PFA1. (b) Stereoview of the overlay of the peptides and CDRs highlights the similarity in binding. PFA1-pep is shown in blue, PFA2-pep is in green. Residues are numbered by the Kabat scheme.
Figure 3.
Fig. 3. Electrostatics of binding. The electrostatic potential surface of PFA1 with bound peptide. Blue represents positive charge, red indicates negative charge, and the apolar surface is shown in white. The A (1–8) peptide is drawn with carbon (yellow), nitrogen (blue), and oxygen (red). Although the Arg 5 residue sits in a pocket of strong negative charge, the Glu 3 residue has no correspondingly positive region around it. This position is susceptible to substitution and cross-reaction.
 
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20842634 A.Teplyakov, G.Obmolova, G.Canziani, Y.Zhao, L.Gutshall, S.S.Jung, and G.L.Gilliland (2011).
His-tag binding by antibody C706 mimics β-amyloid recognition.
  J Mol Recognit, 24, 570-575.
PDB codes: 3mcl 3o11
21499284 Q.Nie, X.G.Du, and M.Y.Geng (2011).
Small molecule inhibitors of amyloid β peptide aggregation as a potential therapeutic strategy for Alzheimer's disease.
  Acta Pharmacol Sin, 32, 545-551.  
20140000 C.A.Lemere, and E.Masliah (2010).
Can Alzheimer disease be prevented by amyloid-beta immunotherapy?
  Nat Rev Neurol, 6, 108-119.  
19923222 G.S.Basi, H.Feinberg, F.Oshidari, J.Anderson, R.Barbour, J.Baker, T.A.Comery, L.Diep, D.Gill, K.Johnson-Wood, A.Goel, K.Grantcharova, M.Lee, J.Li, A.Partridge, I.Griswold-Prenner, N.Piot, D.Walker, A.Widom, M.N.Pangalos, P.Seubert, J.S.Jacobsen, D.Schenk, and W.I.Weis (2010).
Structural correlates of antibodies associated with acute reversal of amyloid beta-related behavioral deficits in a mouse model of Alzheimer disease.
  J Biol Chem, 285, 3417-3427.
PDB codes: 3ifl 3ifn 3ifo 3ifp
20553982 M.Gobbi, F.Re, M.Canovi, M.Beeg, M.Gregori, S.Sesana, S.Sonnino, D.Brogioli, C.Musicanti, P.Gasco, M.Salmona, and M.E.Masserini (2010).
Lipid-based nanoparticles with high binding affinity for amyloid-beta1-42 peptide.
  Biomaterials, 31, 6519-6529.  
20970857 R.Robert, M.P.Lefranc, A.Ghochikyan, M.G.Agadjanyan, D.H.Cribbs, W.E.Van Nostrand, K.L.Wark, and O.Dolezal (2010).
Restricted V gene usage and VH/VL pairing of mouse humoral response against the N-terminal immunodominant epitope of the amyloid β peptide.
  Mol Immunol, 48, 59-72.  
  20920207 S.S.Minami, E.Sidahmed, S.Aid, M.Shimoji, T.Niikura, I.Mocchetti, G.W.Rebeck, J.S.Prendergast, C.Dealwis, R.Wetzel, F.Bosetti, Y.Matsuoka, H.S.Hoe, and R.S.Turner (2010).
Therapeutic versus neuroinflammatory effects of passive immunization is dependent on Aβ/amyloid burden in a transgenic mouse model of Alzheimer's disease.
  J Neuroinflammation, 7, 57.  
19385664 A.Gardberg, L.Dice, K.Pridgen, J.Ko, P.Patterson, S.Ou, R.Wetzel, and C.Dealwis (2009).
Structures of Abeta-related peptide--monoclonal antibody complexes.
  Biochemistry, 48, 5210-5217.
PDB codes: 3eys 3eyu
19690748 A.Rauk (2009).
The chemistry of Alzheimer's disease.
  Chem Soc Rev, 38, 2698-2715.  
19344284 G.A.Jicha (2009).
Is passive immunization for Alzheimer's disease 'alive and well' or 'dead and buried'?
  Expert Opin Biol Ther, 9, 481-491.  
19204293 J.C.Diaz, O.Simakova, K.A.Jacobson, N.Arispe, and H.B.Pollard (2009).
Small molecule blockers of the Alzheimer Abeta calcium channel potently protect neurons from Abeta cytotoxicity.
  Proc Natl Acad Sci U S A, 106, 3348-3353.  
19838688 M.Ionuţ Iuraşcu, C.Cozma, N.Tomczyk, J.Rontree, M.Desor, M.Drescher, and M.Przybylski (2009).
Structural characterization of beta-amyloid oligomer-aggregates by ion mobility mass spectrometry and electron spin resonance spectroscopy.
  Anal Bioanal Chem, 395, 2509-2519.  
19617638 M.Manczak, P.Mao, K.Nakamura, C.Bebbington, B.Park, and P.H.Reddy (2009).
Neutralization of granulocyte macrophage colony-stimulating factor decreases amyloid beta 1-42 and suppresses microglial activity in a transgenic mouse model of Alzheimer's disease.
  Hum Mol Genet, 18, 3876-3893.  
19857116 Z.Ying, W.Xin, H.Jin-Sheng, B.Fu-Xiang, S.Wei-Min, D.Xin-Xian, W.Xiao-Bo, L.Yi-Qin, Z.Xian-Xian, H.Hong-Gang, P.Xiang-Lei, Z.Yan-Peng, H.Ling-Ling, and H.Tao (2009).
Preparation and characterization of a monoclonal antibody with high affinity for soluble Abeta oligomers.
  Hybridoma (Larchmt), 28, 349-354.  
18973685 B.Macao, W.Hoyer, A.Sandberg, A.C.Brorsson, C.M.Dobson, and T.Härd (2008).
Recombinant amyloid beta-peptide production by coexpression with an affibody ligand.
  BMC Biotechnol, 8, 82.  
18407766 M.Steinitz (2008).
Developing injectable immunoglobulins to treat cognitive impairment in Alzheimer's disease.
  Expert Opin Biol Ther, 8, 633-642.  
  18563204 P.B.Rosenberg, and C.Lyketsos (2008).
Mild cognitive impairment: searching for the prodrome of Alzheimer's disease.
  World Psychiatry, 7, 72-78.  
18490917 P.G.Popovich, and E.E.Longbrake (2008).
Can the immune system be harnessed to repair the CNS?
  Nat Rev Neurosci, 9, 481-493.  
18478109 S.B.Raymond, L.H.Treat, J.D.Dewey, N.J.McDannold, K.Hynynen, and B.J.Bacskai (2008).
Ultrasound enhanced delivery of molecular imaging and therapeutic agents in Alzheimer's disease mouse models.
  PLoS ONE, 3, e2175.  
18004559 V.Streltsov (2008).
X-ray absorption and diffraction studies of the metal binding sites in amyloid beta-peptide.
  Eur Biophys J, 37, 257-263.  
18375754 W.Hoyer, C.Grönwall, A.Jonsson, S.Ståhl, and T.Härd (2008).
Stabilization of a beta-hairpin in monomeric Alzheimer's amyloid-beta peptide inhibits amyloid formation.
  Proc Natl Acad Sci U S A, 105, 5099-5104.
PDB code: 2otk
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.