4OD2

Crystal structure of the Fab fragment of an anti-DR5 antibody bound to DR5

4OD2 の概要

• エントリーDOI: 10.2210/pdb4od2/pdb
• 関連するPDBエントリー: 1d0g
• 分子名称: Fab fragment of drozitumab, light chain, Fab fragment of drozitumab, heavy chain, Tumor necrosis factor receptor superfamily member 10B (3 entities in total)
• 機能のキーワード: igg, fab fragment, crd, tnfsf, apoptosis-immune system complex, apoptosis/immune system
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Membrane; Single-pass type I membrane protein: O14763
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 59358.91

構造登録者

Hymowitz, S.G.,Compaan, D. (登録日: 2014-01-09, 公開日: 2014-02-05, 最終更新日: 2024-11-27)

主引用文献

Adams, C.,Totpal, K.,Lawrence, D.,Marsters, S.,Pitti, R.,Yee, S.,Ross, S.,Deforge, L.,Koeppen, H.,Sagolla, M.,Compaan, D.,Lowman, H.,Hymowitz, S.,Ashkenazi, A.
Structural and functional analysis of the interaction between the agonistic monoclonal antibody Apomab and the proapoptotic receptor DR5.
Cell Death Differ., 15:751-761, 2008

PubMed Abstract: Activation of the proapoptotic receptor death receptor5 (DR5) in various cancer cells triggers programmed cell death through the extrinsic pathway. We have generated a fully human monoclonal antibody (Apomab) that induces tumor cell apoptosis through DR5 and investigated the structural features of its interaction with DR5. Biochemical studies showed that Apomab binds DR5 tightly and selectively. X-ray crystallographic analysis of the complex between the Apomab Fab fragment and the DR5 ectodomain revealed an interaction epitope that partially overlaps with both regions of the Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand binding site. Apomab induced DR5 clustering at the cell surface and stimulated a death-inducing signaling complex containing the adaptor molecule Fas-associated death domain and the apoptosis-initiating protease caspase-8. Fc crosslinking further augmented Apomab's proapoptotic activity. In vitro, Apomab triggered apoptosis in cancer cells, while sparing normal hepatocytes even upon anti-Fc crosslinking. In vivo, Apomab exerted potent antitumor activity as a single agent or in combination with chemotherapy in xenograft models, including those based on colorectal, non-small cell lung and pancreatic cancer cell lines. These results provide structural and functional insight into the interaction of Apomab with DR5 and support further investigation of this antibody for cancer therapy.

PubMed: 18219321
DOI: 10.1038/sj.cdd.4402306

実験手法

X-RAY DIFFRACTION (3.2 Å)