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Revision as of 20:12, 16 April 2008

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Template:STRUCTURE 3bkm

Structure of anti-amyloid-beta Fab WO2 (Form A, P212121)

Overview

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.

About this Structure

3BKM is a Protein complex structure of sequences from Mus musculus. Full crystallographic information is available from OCA.

Reference

Amyloid-beta-anti-amyloid-beta complex structure reveals an extended conformation in the immunodominant B-cell epitope., Miles LA, Wun KS, Crespi GA, Fodero-Tavoletti MT, Galatis D, Bagley CJ, Beyreuther K, Masters CL, Cappai R, McKinstry WJ, Barnham KJ, Parker MW, J Mol Biol. 2008 Mar 14;377(1):181-92. Epub 2008 Jan 30. PMID:18237744 Page seeded by OCA on Wed Apr 16 23:12:47 2008