Amyloid-beta-anti-amyloid-beta complex structure reveals an extended conformation in the immunodominant B-cell epitope |
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Authors: | Miles Luke A Wun Kwok S Crespi Gabriela A N Fodero-Tavoletti Michelle T Galatis Denise Bagley Christopher J Beyreuther Konrad Masters Colin L Cappai Roberto McKinstry William J Barnham Kevin J Parker Michael W |
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Affiliation: | 1 Biota Structural Biology Laboratory, St. Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy, Victoria 3065, Australia 2 Department of Chemical and Biomolecular Engineering, The University of Melbourne, Victoria 3010, Australia 3 Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, 30 Flemington Road, Parkville, Victoria 3010, Australia 4 Department of Pathology, The University of Melbourne, Victoria 3010, Australia 5 The Mental Health Research Institute of Victoria, Parkville, Victoria 3052, Australia 6 Hanson Institute, Adelaide, South Australia 5000, Australia 7 Department of Medicine, The University of Adelaide, Adelaide, South Australia 5005, Australia 8 ZMBH, University of Heidelberg, D-69120 Heidelberg, Germany |
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Abstract: | Alzheimer's disease (AD) is the most common form of dementia. Amyloid-β (Aβ) peptide, generated by proteolytic cleavage of the amyloid precursor protein, is central to AD pathogenesis. Most pharmaceutical activity in AD research has focused on Aβ, its generation and clearance from the brain. In particular, there is much interest in immunotherapy approaches with a number of anti-Aβ antibodies in clinical trials. We have developed a monoclonal antibody, called WO2, which recognises the Aβ 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 Aβ peptide. The structures reveal the molecular basis for WO2 recognition and binding of Aβ. The Aβ 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 Aβ 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 Aβ, such as WO2, hold promise for therapeutic development. |
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Keywords: | Aβ, peptide associated with Alzheimer's disease AD, Alzheimer's disease CDR, complementarity determining region L1-3, light-chain CDR 1-3 H1-3, heavy-chain CDR 1-3 mAb, monoclonal antibody r.m.s.d., root-mean-square deviation WO2, antibody raised against Aβ NMR, nuclear magnetic resonance PDB, Protein Data Bank Ig, immunoglobulin MALDI-TOF, matrix-assisted laser desorption/ionisation time of flight MS, mass spectrometry MWCO, molecular weight cutoff RACE, rapid amplification of cDNA ends LC, liquid chromatography Mes, 4-morpholineethanesulfonic acid MME, monomethyl ether PEG, polyethylene glycol |
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