2IPU

PFA1 Fab fragment complexed with Abeta 1-8 peptide

2IPU の概要

• エントリーDOI: 10.2210/pdb2ipu/pdb
• 関連するPDBエントリー: 2IPT 2IQ9 2IQA 2IQB
• 分子名称: IgG2a Fab fragment Heavy Chain, IgG2a Fab fragment Light Chain Kappa, abeta 1-8 peptide, ... (6 entities in total)
• 機能のキーワード: wwddd, cdr, abeta, immune system
• 由来する生物種: Mus musculus (house mouse); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 99169.57

構造登録者

Gardberg, A.S.,Dealwis, C. (登録日: 2006-10-12, 公開日: 2007-10-09, 最終更新日: 2024-10-30)

主引用文献

Gardberg, A.S.,Dice, L.T.,Ou, S.,Rich, R.L.,Helmbrecht, E.,Ko, J.,Wetzel, R.,Myszka, D.G.,Patterson, P.H.,Dealwis, C.
Molecular basis for passive immunotherapy of Alzheimer's disease
Proc.Natl.Acad.Sci.Usa, 104:15659-15664, 2007

PubMed Abstract: 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.

PubMed: 17895381
DOI: 10.1073/pnas.0705888104

実験手法

X-RAY DIFFRACTION (1.65 Å)