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Publication Abstract from PubMed

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 Abeta N-terminus. The monoclonal anti-Abeta Ab PFA1 recognizes the EFRH epitope of Abeta. PFA1 has a high affinity for Abeta fibrils and protofibrils (0.1 nM), as well as good affinity for Abeta monomers (20 nM). However, PFA1 binds the toxic N-terminally modified pyro-glutamate peptide pyro-Glu3-Abeta with a 77-fold loss in affinity compared to the WT Abeta(1-8). Furthermore, our earlier work illustrated PFA-1's potential for cross-reactivity. The receptor tyrosine kinaseRor2 which plays a role in skeletal and bone formation possesses the EFRH sequence. In fact, the PFA1 Fab binds the Ror2 peptide REEFRHEA with a 3-fold enhancement over WT Abeta(1-8). In this paper, the crystal structures of the hybridoma-derived PFA1 Fab in complex with pyro-Glu3-Abetapeptide and with a cross-reacting peptide from Ror2 have been determined at resolutions of 1.95 and 2.7 A, respectively. As with wild type Abeta, 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 Abeta(1-8), Grip1, pyro-Glu3-Abeta and Ror2 in complex with PFA-1 show that the greatest conformational flexibility occur at residues 2-3 and 8 of the peptide. These structures provide a molecular basis of the specificity tolerance of PFA1, and its ability to recognize Abeta N-terminal heterogeneity. The structures provide clues to improving mAb specificity and affinity for pyro-Glutamate Abeta.

THE X-RAY STRUCTURES OF AMYLOID BETA-RELATED PEPTIDES COMPLEXED TO ANTIBODIES.,Gardberg AS, Dice L, Pridgen K, Ko J, Patterson P, Ou S, Wetzel R, Dealwis C Biochemistry. 2009 Apr 22. PMID:19385664^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.