Conformational effects of N-glycan core fucosylation of immunoglobulin G Fc region on its interaction with Fcγ receptor IIIa.
Conformational effects of N-glycan core fucosylation of immunoglobulin G Fc region on its interaction with Fcγ receptor IIIa.
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DOI：
10.1038/s41598-017-13845-8
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发表时间：
2017-10-23
影响因子：
4.6
通讯作者：
Kato K
中科院分区：
文献类型：
--
作者：
Sakae Y;Satoh T;Yagi H;Yanaka S;Yamaguchi T;Isoda Y;Iida S;Okamoto Y;Kato K
抗体依赖性细胞毒性（ADCC）是通过免疫球蛋白G1 （IgG1）的Fc区和Fcγ受体IIIa （Fcγ riiia）之间的相互作用而促进的，这取决于这些糖蛋白的n -糖基化。特别是，IgG1-Fc n -聚糖的核心聚焦会对这种相互作用产生负面影响，从而损害ADCC的活性。为了解决这种效应的机制，我们基于与IgG1-Fc配合物的可溶形式fc - γ riiia （sfc - γ riiia）的晶体学分析进行了复制交换分子动力学模拟。我们的模拟显示，在IgG1-Fc的聚焦作用下，sFcγRIIIa的Asn162处的n -聚糖的构象波动增加，这与晶体学数据一致，除了最内部的部分外，没有给出该n -聚糖的可解释电子密度。聚焦残基破坏了最佳的分子间碳水化合物-碳水化合物相互作用，使该sFcγRIIIa聚糖远离Fc聚糖。此外，我们的模拟表明，IgG1-Fc的核心聚焦会影响构象动力学和周围氨基酸残基的重排，以IgG1-Fc的Tyr296为代表，它更广泛地参与了与sFcγRIIIa的相互作用，而没有Fc核心聚焦。我们的发现为设计和开发具有改善ADCC活性的治疗性抗体提供了结构基础。
Antibody-dependent cellular cytotoxicity (ADCC) is promoted through interaction between the Fc region of immunoglobulin G1 (IgG1) and Fcγ receptor IIIa (FcγRIIIa), depending on N-glycosylation of these glycoproteins. In particular, core fucosylation of IgG1-Fc N-glycans negatively affects this interaction and thereby compromises ADCC activity. To address the mechanisms of this effect, we performed replica-exchange molecular dynamics simulations based on crystallographic analysis of a soluble form of FcγRIIIa (sFcγRIIIa) in complex with IgG1-Fc. Our simulation highlights increased conformational fluctuation of the N-glycan at Asn162 of sFcγRIIIa upon fucosylation of IgG1-Fc, consistent with crystallographic data giving no interpretable electron density for this N-glycan, except for the innermost part. The fucose residue disrupts optimum intermolecular carbohydrate-carbohydrate interactions, rendering this sFcγRIIIa glycan distal from the Fc glycan. Moreover, our simulation demonstrates that core fucosylation of IgG1-Fc affects conformational dynamics and rearrangements of surrounding amino acid residues, typified by Tyr296 of IgG1-Fc, which was more extensively involved in the interaction with sFcγRIIIa without Fc core fucosylation. Our findings offer a structural foundation for designing and developing therapeutic antibodies with improved ADCC activity.
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影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML
影响因子：
3.7
作者：
Isoda Y;Yagi H;Satoh T;Shibata-Koyama M;Masuda K;Satoh M;Kato K;Iida S
通讯作者：
Iida S
影响因子：
3.2
作者：
Suzuki, Tatsuya;Kajino, Megumi;Kato, Koichi
通讯作者：
Kato, Koichi
DOI：
10.1107/s0907444910007493
发表时间：
2010-04
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Emsley P;Lohkamp B;Scott WG;Cowtan K
通讯作者：
Cowtan K
DOI：
10.1111/j.1365-2443.2011.01552.x
发表时间：
2011-11
期刊：
Genes to cells : devoted to molecular & cellular mechanisms
影响因子：
--
作者：
Mizushima T;Yagi H;Takemoto E;Shibata-Koyama M;Isoda Y;Iida S;Masuda K;Satoh M;Kato K
通讯作者：
Kato K