5VZY

Crystal structure of crenezumab Fab in complex with Abeta

「5KNA」から置き換えられました

5VZY の概要

• エントリーDOI: 10.2210/pdb5vzy/pdb
• 関連するPDBエントリー: 5VZX
• 分子名称: Crenezumab Fab heavy chain,Immunoglobulin gamma-1 heavy chain, Crenezumab Fab light chain,Immunoblobulin light chain, Amyloid beta A4 protein, ... (4 entities in total)
• 機能のキーワード: immunoglobulin, immune system
• 由来する生物種: Homo sapiens; 詳細
• 細胞内の位置: Secreted : P0DOX5; Membrane; Single-pass type I membrane protein: P05067
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 48820.30

構造登録者

Ultsch, M.,Wang, W. (登録日: 2017-05-29, 公開日: 2017-08-09, 最終更新日: 2024-10-09)

主引用文献

Ultsch, M.,Li, B.,Maurer, T.,Mathieu, M.,Adolfsson, O.,Muhs, A.,Pfeifer, A.,Pihlgren, M.,Bainbridge, T.W.,Reichelt, M.,Ernst, J.A.,Eigenbrot, C.,Fuh, G.,Atwal, J.K.,Watts, R.J.,Wang, W.
Structure of Crenezumab Complex with Abeta Shows Loss of beta-Hairpin.
Sci Rep, 6:39374-, 2016

PubMed Abstract: Accumulation of amyloid-β (Aβ) peptides and amyloid plaque deposition in brain is postulated as a cause of Alzheimer's disease (AD). The precise pathological species of Aβ remains elusive although evidence suggests soluble oligomers may be primarily responsible for neurotoxicity. Crenezumab is a humanized anti-Aβ monoclonal IgG4 that binds multiple forms of Aβ, with higher affinity for aggregated forms, and that blocks Aβ aggregation, and promotes disaggregation. To understand the structural basis for this binding profile and activity, we determined the crystal structure of crenezumab in complex with Aβ. The structure reveals a sequential epitope and conformational requirements for epitope recognition, which include a subtle but critical element that is likely the basis for crenezumab's versatile binding profile. We find interactions consistent with high affinity for multiple forms of Aβ, particularly oligomers. Of note, crenezumab also sequesters the hydrophobic core of Aβ and breaks an essential salt-bridge characteristic of the β-hairpin conformation, eliminating features characteristic of the basic organization in Aβ oligomers and fibrils, and explains crenezumab's inhibition of aggregation and promotion of disaggregation. These insights highlight crenezumab's unique mechanism of action, particularly regarding Aβ oligomers, and provide a strong rationale for the evaluation of crenezumab as a potential AD therapy.

PubMed: 27996029
DOI: 10.1038/srep39374

実験手法

X-RAY DIFFRACTION (2.32 Å)