2r0w

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Revision as of 21:29, 12 November 2007

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spinqualitylabelsall models 2r0w, resolution 2.503Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

PFA2 FAB complexed with Abeta1-8

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

Amyloid aggregates of the amyloid-beta (Abeta) peptide are implicated in, the pathology of Alzheimer's disease. Anti-Abeta monoclonal antibodies, (mAbs) have been shown to reduce amyloid plaques in vitro and in animal, studies. Consequently, passive immunization is being considered for, treating Alzheimer's, and anti-Abeta mAbs are now in phase II trials. We, report the isolation of two mAbs (PFA1 and PFA2) that recognize Abeta, monomers, protofibrils, and fibrils and the structures of their antigen, binding fragments (Fabs) in complex with the Abeta(1-8) peptide DAEFRHDS., The immunodominant EFRHD sequence forms salt bridges, hydrogen bonds, and, hydrophobic contacts, including interactions with a striking WWDDD motif, of the antigen binding fragments. We also show that a similar sequence, (AKFRHD) derived from the human protein GRIP1 is able to cross-react with, both PFA1 and PFA2 and, when cocrystallized with PFA1, binds in an, identical conformation to Abeta(1-8). Because such cross-reactivity has, implications for potential side effects of immunotherapy, our structures, provide a template for designing derivative mAbs that target Abeta with, improved specificity and higher affinity.

Disease

Known diseases associated with this structure: Alzheimer disease-1, APP-related OMIM:[104760], Amyloidosis, cerebroarterial, Dutch type OMIM:[104760], Amyloidosis, cerebroarterial, Iowa type OMIM:[104760], Blood group, P system OMIM:[607922]

About this Structure

2R0W is a Protein complex structure of sequences from Mus musculus with NA as ligand. Full crystallographic information is available from OCA.

Reference

Molecular basis for passive immunotherapy of Alzheimer's disease., Gardberg AS, Dice LT, Ou S, Rich RL, Helmbrecht E, Ko J, Wetzel R, Myszka DG, Patterson PH, Dealwis C, Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15659-64. Epub 2007 Sep 25. PMID:17895381

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