PDBsum entry 2ipu

Immune system

PDB id: 2ipu

Contents

Protein chains

219 a.a.

223 a.a.

Ligands

ALA-GLU-PHE-ARG-HIS-ASP-SER ×2

ACM ×3

GOL ×6

Waters ×118

References listed in PDB file

Key reference

Title

Molecular basis for passive immunotherapy of alzheimer'S disease.

Authors

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.

Ref.

Proc Natl Acad Sci U S A, 2007, 104, 15659-15664. [DOI no: 10.1073/pnas.0705888104]

PubMed id

17895381

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.

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.