Atomic resolution model of the antibody Fc interaction with the complement C1q component.
Atomic resolution model of the antibody Fc interaction with the complement C1q component.
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DOI：
10.1016/j.molimm.2012.02.111
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发表时间：
2012-05
影响因子：
3.6
通讯作者：
S. Schneider;M. Zacharias
中科院分区：
文献类型：
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作者：
S. Schneider;M. Zacharias
球状 C1q 异三聚体是 C1 补体因子的一个亚基。 C1q 亚基与抗体分子恒定 (Fc) 部分的结合是补体激活的第一步和关键事件。尽管 C1q 和抗体 Fc 亚基的三维结构已通过实验确定，但迄今为止尚不清楚 C1q-Fc 复合物的原子分辨率结构。基于系统的蛋白质-蛋白质对接搜索和分子动力学模拟，获得了 C1q-IgG1-Fc 结合几何结构的结构模型。该结构模型与两种伙伴蛋白之间相互作用的现有实验数据兼容。它预测的结合几何结构主要涉及 C1q 三聚体的 B 亚基和 IgG1-Fc 二聚体的两个亚基，相对于未结合的配偶体进行较小的构象调整，以实现高表面互补性。除了界面边缘区域的几个电荷-电荷和极性接触之外，它还涉及两种蛋白质之间的非极性接触，并且与 Fc 亚基的碳水化合物部分相容。复杂结构的模型为合理化有关这一重要相互作用的现有生化数据提供了一个工作模型，并且可以构成设计具有更大能力激活补体系统（例如与癌细胞或其他靶结构结合）的 Fc 变体的基础。
The globular C1q heterotrimer is a subunit of the C1 complement factor. Binding of the C1q subunit to the constant (Fc) part of antibody molecules is a first step and key event of complement activation. Although three-dimensional structures of C1q and antibody Fc subunits have been determined experimentally no atomic resolution structure of the C1q–Fc complex is known so far. Based on systematic protein–protein docking searches and Molecular Dynamics simulations a structural model of the C1q–IgG1–Fc-binding geometry has been obtained. The structural model is compatible with available experimental data on the interaction between the two partner proteins. It predicts a binding geometry that involves mainly the B-subunit of the C1q-trimer and both subunits of the IgG1–Fc-dimer with small conformational adjustments with respect to the unbound partners to achieve high surface complementarity. In addition to several charge–charge and polar contacts in the rim region of the interface it also involves nonpolar contacts between the two proteins and is compatible with the carbohydrate moiety of the Fc subunit. The model for the complex structure provides a working model for rationalizing available biochemical data on this important interaction and can form the basis for the design of Fc variants with a greater capacity to activate the complement system for example on binding to cancer cells or other target structures.