3SGK

Unique carbohydrate/carbohydrate interactions are required for high affinity binding of FcgIII and antibodies lacking core fucose

3SGK の概要

• エントリーDOI: 10.2210/pdb3sgk/pdb
• 関連するPDBエントリー: 3SGJ
• 分子名称: Fc fragment, human Fcg3a receptor, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[2-acetamido-2-deoxy-beta-D-glucopyranose-(1-2)-alpha-D-mannopyranose-(1-6)][2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• 機能のキーワード: fc receptor, antibody, afucosylation, immune system
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 79022.16

構造登録者

Ferrara, C.,Grau, S.,Jaeger, C.,Sondermann, P.,Bruenker, P.,Waldhauer, I.,Hennig, M.,Ruf, A.,Rufer, A.C.,Stihle, M.,Umana, P.,Benz, J. (登録日: 2011-06-15, 公開日: 2011-08-03, 最終更新日: 2024-12-25)

主引用文献

Ferrara, C.,Grau, S.,Jager, C.,Sondermann, P.,Brunker, P.,Waldhauer, I.,Hennig, M.,Ruf, A.,Rufer, A.C.,Stihle, M.,Umana, P.,Benz, J.
Unique carbohydrate-carbohydrate interactions are required for high affinity binding between FcgammaRIII and antibodies lacking core fucose.
Proc.Natl.Acad.Sci.USA, 108:12669-12674, 2011

PubMed Abstract: Antibody-mediated cellular cytotoxicity (ADCC), a key immune effector mechanism, relies on the binding of antigen-antibody complexes to Fcγ receptors expressed on immune cells. Antibodies lacking core fucosylation show a large increase in affinity for FcγRIIIa leading to an improved receptor-mediated effector function. Although afucosylated IgGs exist naturally, a next generation of recombinant therapeutic, glycoenginereed antibodies is currently being developed to exploit this finding. In this study, the crystal structures of a glycosylated Fcγ receptor complexed with either afucosylated or fucosylated Fc were determined allowing a detailed, molecular understanding of the regulatory role of Fc-oligosaccharide core fucosylation in improving ADCC. The structures reveal a unique type of interface consisting of carbohydrate-carbohydrate interactions between glycans of the receptor and the afucosylated Fc. In contrast, in the complex structure with fucosylated Fc, these contacts are weakened or nonexistent, explaining the decreased affinity for the receptor. These findings allow us to understand the higher efficacy of therapeutic antibodies lacking the core fucose and also suggest a unique mechanism by which the immune system can regulate antibody-mediated effector functions.

PubMed: 21768335
DOI: 10.1073/pnas.1108455108

実験手法

X-RAY DIFFRACTION (2.4 Å)