Epitopes described in "Amyloid-beta-anti-amyloid-beta complex structure reveals an extended conformation in the immunodominant B-cell epitope."

Article Authors:Luke A Miles; Kwok S Wun; Gabriela A N Crespi; Michelle T Fodero-Tavoletti; Denise Galatis; Christopher J Bagley; Konrad Beyreuther; Colin L Masters; Roberto Cappai; William J McKinstry; Kevin J Barnham; Michael W Parker
Article Title:Amyloid-beta-anti-amyloid-beta complex structure reveals an extended conformation in the immunodominant B-cell epitope.
Reference Detail
Reference ID:1010612
Abstract:Alzheimer's disease (AD) is the most common form of dementia. Amyloid-beta (A beta) peptide, generated by proteolytic cleavage of the amyloid precursor protein, is central to AD pathogenesis. Most pharmaceutical activity in AD research has focused on A beta, its generation and clearance from the brain. In particular, there is much interest in immunotherapy approaches with a number of anti-A beta antibodies in clinical trials. We have developed a monoclonal antibody, called WO2, which recognises the A beta peptide. To this end, we have determined the three-dimensional structure, to near atomic resolution, of both the antibody and the complex with its antigen, the A beta peptide. The structures reveal the molecular basis for WO2 recognition and binding of A beta. The A beta peptide adopts an extended, coil-like conformation across its major immunodominant B-cell epitope between residues 2 and 8. We have also studied the antibody-bound A beta peptide in the presence of metals known to affect its aggregation state and show that WO2 inhibits these interactions. Thus, antibodies that target the N-terminal region of A beta, such as WO2, hold promise for therapeutic development.
Affiliations:Biota Structural Biology Laboratory, St. Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy, Victoria 3065, Australia.
Reference Type:Literature
PubMed ID:18237744
Journal:J Mol Biol
Journal Volume:377
Article Pages:181-92
Journal ISSN:1089-8638
Article Chemical List:Amyloid beta-Peptides;Antibodies, Monoclonal;Complementarity Determining Regions;Epitopes, B-Lymphocyte;Immunodominant Epitopes;Immunoglobulin Fab Fragments;Ligands;Metals
Article MeSH List:Amyloid beta-Peptides(chemistry; immunology); Animals; Antibodies, Monoclonal(immunology); Complementarity Determining Regions(chemistry); Crystallography, X-Ray; Epitopes, B-Lymphocyte(chemistry; immunology); Immunodominant Epitopes(chemistry; immunology); Immunoglobulin Fab Fragments(chemistry; immunology); Ligands; Metals; Mice; Models, Molecular; Protein Structure, Secondary; Software; Surface Properties; Temperature
Curation Last Updated:2014-10-03 21:06:29