溶液中免疫球蛋白 Fc 结构域的构象可塑性。
Conformational Plasticity of the Immunoglobulin Fc Domain in Solution.
机构信息
Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
Janssen BioTherapeutics, Janssen R&D, LLC, Spring House, PA 19477, USA.
出版信息
Structure. 2018 Jul 3;26(7):1007-1014.e2. doi: 10.1016/j.str.2018.03.017. Epub 2018 May 3.
Fragment crystallizable (Fc) region of immunoglobulin G (IgG) antibody binds to specific Fc receptors (FcγRs) to control antibody effector functions. Currently, engineered specific Fc-FcγR interactions are validated with a static conformation derived from the crystal structure. However, computational evidence suggests that the conformational variability of Fcs plays an important role in receptor recognition. Here we elucidate Fc flexibility of IgG1, IgG2, and IgG1 Fc with mutations (M255Y/S257T/T259E) in solution by small-angle X-ray scattering (SAXS). Measured SAXS profiles and experimental parameters show variations in flexibility between Fc isotypes. We develop and apply a modeling tool for an accurate conformational sampling of Fcs followed by SAXS fitting. Revealed conformational variability of the CH2 domain as low as 10 Å in displacement, illustrates the power of the atomistic modeling combined with SAXS. This inexpensive SAXS-based approach offers to improve the engineering of antibodies for tailoring Fc receptor interactions through altering and measuring Fc flexibility.
免疫球蛋白 G（IgG）抗体的 Fc 区与特定的 Fc 受体（FcγRs）结合，以控制抗体效应功能。目前，工程化的特定 Fc-FcγR 相互作用是通过源自晶体结构的静态构象来验证的。然而，计算证据表明 Fc 的构象可变性在受体识别中起着重要作用。在这里，我们通过小角度 X 射线散射（SAXS）阐明了 IgG1、IgG2 和 IgG1 Fc 中突变（M255Y/S257T/T259E）在溶液中的 Fc 灵活性。测量的 SAXS 图谱和实验参数显示了 Fc 同型之间的灵活性差异。我们开发并应用了一种建模工具，用于对 Fc 进行准确的构象采样，然后进行 SAXS 拟合。所揭示的 CH2 结构域的构象可变性低至 10Å，说明了原子建模与 SAXS 相结合的强大功能。这种基于 SAXS 的廉价方法提供了一种改进方法，可通过改变和测量 Fc 灵活性来设计抗体以定制 Fc 受体相互作用。
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