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TitleConformational Plasticity of the Immunoglobulin Fc Domain in Solution.
Journal, issue, pagesStructure, Vol. 26, Issue 7, Page 1007-11014.e2, Year 2018
Publish dateJul 3, 2018
AuthorsSoumya G Remesh / Anthony A Armstrong / Andrew D Mahan / Jinquan Luo / Michal Hammel /
PubMed AbstractFragment crystallizable (Fc) region of immunoglobulin G (IgG) antibody binds to specific Fc receptors (FcγRs) to control antibody effector functions. Currently, engineered specific Fc-FcγR ...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.
External linksStructure / PubMed:29731233 / PubMed Central
MethodsSAS (X-ray synchrotron)
Structure data

SASDDT4:
Fc region of Immunoglobulin G1 (IgG1 Fc) (Immunoglobulin heavy constant gamma 1, IgG1 Fc)
Method: SAXS/SANS

SASDDU4:
Fc region of Immunoglobulin G2 (IgG2 Fc) (Immunoglobulin heavy constant gamma 2, IgG2 Fc S257A)
Method: SAXS/SANS

SASDDV4:
Fc-region of Immunoglobulin G1, M135Y/S137T/T139E mutant (IgG1 Fc-YTE)
Method: SAXS/SANS

Source
  • Homo sapiens (human)

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