4TRP

Crystal structure of monoclonal antibody against neuroblastoma associated antigen.

4TRP の概要

• エントリーDOI: 10.2210/pdb4trp/pdb
• 分子名称: Heavy chain of monoclonal antibody against neuroblastoma associated antigen, Light chain of monoclonal antibody against neuroblastoma associated antigen (3 entities in total)
• 機能のキーワード: antibody, 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: 2
• 化学式量合計: 47000.42

構造登録者

Horwacik, I.,Golik, P.,Grudnik, P.,Zdzalik, M.,Rokita, H.,Dubin, G. (登録日: 2014-06-17, 公開日: 2015-07-15, 最終更新日: 2024-11-06)

主引用文献

Horwacik, I.,Golik, P.,Grudnik, P.,Kolinski, M.,Zdzalik, M.,Rokita, H.,Dubin, G.
Structural Basis of GD2 Ganglioside and Mimetic Peptide Recognition by 14G2a Antibody.
Mol.Cell Proteomics, 14:2577-2590, 2015

PubMed Abstract: Monoclonal antibodies targeting GD2 ganglioside (GD2) have recently been approved for the treatment of high risk neuroblastoma and are extensively evaluated in clinics in other indications. This study illustrates how a therapeutic antibody distinguishes between different types of gangliosides present on normal and cancer cells and informs how synthetic peptides can imitate ganglioside in its binding to the antibody. Using high resolution crystal structures we demonstrate that the ganglioside recognition by a model antibody (14G2a) is based primarily on an extended network of direct and water molecule mediated hydrogen bonds. Comparison of the GD2-Fab structure with that of a ligand free antibody reveals an induced fit mechanism of ligand binding. These conclusions are validated by directed mutagenesis and allowed structure guided generation of antibody variant with improved affinity toward GD2. Contrary to the carbohydrate, both evaluated mimetic peptides utilize a "key and lock" interaction mechanism complementing the surface of the antibody binding groove exactly as found in the empty structure. The interaction of both peptides with the Fab relies considerably on hydrophobic contacts however, the detailed connections differ significantly between the peptides. As such, the evaluated peptide carbohydrate mimicry is defined primarily in a functional and not in structural manner.

PubMed: 26179345
DOI: 10.1074/mcp.M115.052720

実験手法

X-RAY DIFFRACTION (1.25 Å)