3WN5

Crystal structure of asymmetrically engineered Fc variant in complex with FcgRIIIa

3WN5 の概要

• エントリーDOI: 10.2210/pdb3wn5/pdb
• 分子名称: Ig gamma-1 chain C region, Low affinity immunoglobulin gamma Fc region receptor III-A, beta-D-galactopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-2)-alpha-D-mannopyranose-(1-6)-[2-acetamido-2-deoxy-beta-D-glucopyranose-(1-2)-alpha-D-mannopyranose-(1-3)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[beta-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (10 entities in total)
• 機能のキーワード: receptor complex, fc receptor, antibody, immune system
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 159759.31

構造登録者

Kadono, S.,Mimoto, F.,Katada, H.,Igawa, T.,Kamikawa, T.,Hattori, K. (登録日: 2013-12-05, 公開日: 2014-11-19, 最終更新日: 2024-11-06)

主引用文献

Mimoto, F.,Kadono, S.,Katada, H.,Igawa, T.,Kamikawa, T.,Hattori, K.
Crystal structure of a novel asymmetrically engineered Fc variant with improved affinity for Fc gamma Rs.
Mol.Immunol., 58:132-138, 2014

PubMed Abstract: Enhancing the effector function by optimizing the interaction between Fc and Fcγ receptor (FcγR) is a promising approach to enhance the potency of anticancer monoclonal antibodies (mAbs). To date, a variety of Fc engineering approaches to modulate the interaction have been reported, such as afucosylation in the heavy chain Fc region or symmetrically introducing amino acid substitutions into the region, and there is still room to improve FcγR binding and thermal stability of the CH2 domain with these approaches. Recently, we have reported that asymmetric Fc engineering, which introduces different substitutions into each Fc region of heavy chain, can further improve the FcγR binding while maintaining the thermal stability of the CH2 domain by fine-tuning the asymmetric interface between the Fc domain and FcγR. However, the structural mechanism by which the asymmetrically engineered Fc improved FcγR binding remained unclear. In order to elucidate the mechanism, we solved the crystal structure of a novel asymmetrically engineered Fc, asym-mAb23, in complex with FcγRIIIa. Asym-mAb23 has enhanced binding affinity for both FcγRIIIa and FcγRIIa at the highest level of previously reported Fc variants. The structural analysis reveals the features of the asymmetrically engineered Fc in comparison with symmetric Fc and how each asymmetrically introduced substitution contributes to the improved interaction between asym-mAb23 and FcγRIIIa. This crystal structure could be utilized to enable us to design a more potent asymmetric Fc.

PubMed: 24334029
DOI: 10.1016/j.molimm.2013.11.017

実験手法

X-RAY DIFFRACTION (2.78 Å)