Structures of A[beta]-Related Peptide−Monoclonal Antibody Complexes
Passive immunotherapy (PI) is being explored as a potential therapeutic against Alzheimer's disease. The most promising antibodies (Abs) used in PI target the EFRH motif of the A{beta} N-terminus. The monoclonal anti-A{beta} Ab PFA1 recognizes the EFRH epitope of A{beta}. PFA1 has a high affinity for A{beta} fibrils and protofibrils (0.1 nM), as well as good affinity for A{beta} monomers (20 nM). However, PFA1 binds the toxic N-terminally modified pyroglutamate peptide pyro-Glu3-A{beta} with a 77-fold loss in affinity compared to the WT A{beta}(1-8). Furthermore, our earlier work illustrated PFA1's potential for cross-reactivity. The receptor tyrosine kinase Ror2, which plays a role in skeletal and bone formation, possesses the EFRH sequence. PFA1 Fab binds the Ror2(518-525) peptide sequence REEFRHEA with a 3-fold enhancement over WT A{beta}(1-8). In this work, the crystal structures of the hybridoma-derived PFA1 Fab in complex with pyro-Glu3-A{beta} peptide and with a cross-reacting peptide from Ror2 have been determined at resolutions of 1.95 and 2.7 {angstrom}, respectively. As with wild-type A{beta}, these peptides bind to the Fab via a combination of charge- and shape-complementarity, hydrogen-bonding, and hydrophobic interactions. Comparison of the structures of the four peptides A{beta}(1-8), Grip1, pyro-Glu3-A{beta}(3-8), and Ror2 in complex with PFA1 shows that the greatest conformational flexibility occurs at residues 2 to 3 and 8 of the peptide. These structures provide a molecular basis of the specificity tolerance of PFA1 and its ability to recognize A{beta} N-terminal heterogeneity. The structures provide clues to improving mAb specificity and affinity for pyroglutamate A{beta}.
- Research Organization:
- Argonne National Lab. (ANL), Argonne, IL (United States)
- Sponsoring Organization:
- USDOE
- OSTI ID:
- 1005674
- Journal Information:
- Biochemistry-US, Vol. 48, Issue (23) ; 06, 2009; ISSN 0006-2960
- Country of Publication:
- United States
- Language:
- ENGLISH
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