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Title: Conformational Plasticity of the Immunoglobulin Fc Domain in Solution

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. Furthermore, this inexpensive SAXS-based approach offers to improve the engineering of antibodies for tailoring Fc receptor interactions through altering and measuring Fc flexibility.
Authors:
 [1] ;  [2] ;  [2] ;  [2] ;  [1]
  1. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  2. Janssen R&D, LLC, Spring House, PA (United States)
Publication Date:
Grant/Contract Number:
AC02-05CH11231
Type:
Accepted Manuscript
Journal Name:
Structure
Additional Journal Information:
Journal Volume: 26; Journal Issue: 7; Journal ID: ISSN 0969-2126
Publisher:
Elsevier
Research Org:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; immunoglobulin G antibody (IgG); fragment crystallizable (Fc) region; small angle X-ray scattering; SAXS; conformational flexibility; glycoprotein; rigid body modeling; BILBOMD
OSTI Identifier:
1484214

Remesh, Soumya G., Armstrong, Anthony A., Mahan, Andrew D., Luo, Jinquan, and Hammel, Michal. Conformational Plasticity of the Immunoglobulin Fc Domain in Solution. United States: N. p., Web. doi:10.1016/j.str.2018.03.017.
Remesh, Soumya G., Armstrong, Anthony A., Mahan, Andrew D., Luo, Jinquan, & Hammel, Michal. Conformational Plasticity of the Immunoglobulin Fc Domain in Solution. United States. doi:10.1016/j.str.2018.03.017.
Remesh, Soumya G., Armstrong, Anthony A., Mahan, Andrew D., Luo, Jinquan, and Hammel, Michal. 2018. "Conformational Plasticity of the Immunoglobulin Fc Domain in Solution". United States. doi:10.1016/j.str.2018.03.017. https://www.osti.gov/servlets/purl/1484214.
@article{osti_1484214,
title = {Conformational Plasticity of the Immunoglobulin Fc Domain in Solution},
author = {Remesh, Soumya G. and Armstrong, Anthony A. and Mahan, Andrew D. and Luo, Jinquan and Hammel, Michal},
abstractNote = {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. Furthermore, this inexpensive SAXS-based approach offers to improve the engineering of antibodies for tailoring Fc receptor interactions through altering and measuring Fc flexibility.},
doi = {10.1016/j.str.2018.03.017},
journal = {Structure},
number = 7,
volume = 26,
place = {United States},
year = {2018},
month = {5}
}