Conformational Plasticity of the Immunoglobulin Fc Domain in Solution

Remesh, Soumya G.; Armstrong, Anthony A.; Mahan, Andrew D.; Luo, Jinquan; Hammel, Michal

doi:10.1016/j.str.2018.03.017

Title: Conformational Plasticity of the Immunoglobulin Fc Domain in Solution

Abstract

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:: Remesh, Soumya G.; Armstrong, Anthony A.; Mahan, Andrew D.; Luo, Jinquan; Hammel, Michal

Publication Date:: Sun Jul 01 00:00:00 EDT 2018

Research Org.:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Org.:: USDOE Office of Science (SC), Biological and Environmental Research (BER)

OSTI Identifier:: 1562946

Alternate Identifier(s):: OSTI ID: 1484214

Grant/Contract Number:: AC02-05CH11231

Resource Type:: Published Article

Journal Name:: Structure

Additional Journal Information:: Journal Name: Structure Journal Volume: 26 Journal Issue: 7; Journal ID: ISSN 0969-2126

Publisher:: Elsevier

Country of Publication:: United Kingdom

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

Citation Formats


                    Remesh, Soumya G., Armstrong, Anthony A., Mahan, Andrew D., Luo, Jinquan, and Hammel, Michal. Conformational Plasticity of the Immunoglobulin Fc Domain in Solution.  United Kingdom: N. p., 2018. 
Web.  doi:10.1016/j.str.2018.03.017.

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                    Remesh, Soumya G., Armstrong, Anthony A., Mahan, Andrew D., Luo, Jinquan, & Hammel, Michal. Conformational Plasticity of the Immunoglobulin Fc Domain in Solution.  United Kingdom.  https://doi.org/10.1016/j.str.2018.03.017

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                    Remesh, Soumya G., Armstrong, Anthony A., Mahan, Andrew D., Luo, Jinquan, and Hammel, Michal. Sun .  
"Conformational Plasticity of the Immunoglobulin Fc Domain in Solution".  United Kingdom.  https://doi.org/10.1016/j.str.2018.03.017.

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@article{osti_1562946,

  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 Kingdom},

  year         = {Sun Jul 01 00:00:00 EDT 2018},

  month        = {Sun Jul 01 00:00:00 EDT 2018}

}

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Works referencing / citing this record:

Dynamic Views of the Fc Region of Immunoglobulin G Provided by Experimental and Computational Observations
journal, July 2019

Yanaka, Saeko; Yogo, Rina; Inoue, Rintaro
Antibodies, Vol. 8, Issue 3
DOI: 10.3390/antib8030039

Dynamic Views of the Fc Region of Immunoglobulin G Provided by Experimental and Computational Observations
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Yanaka, Saeko; Yogo, Rina; Inoue, Rintaro
Antibodies, Vol. 8, Issue 3
DOI: 10.3390/antib8030039

Probing Conformational Diversity of Fc Domains in Aggregation-Prone Monoclonal Antibodies
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Majumder, Subhabrata; Jones, Michael T.; Kimmel, Michael
Pharmaceutical Research, Vol. 35, Issue 11
DOI: 10.1007/s11095-018-2500-8

C _H 2 domain orientation of human immunoglobulin G in solution: Structural comparison of glycosylated and aglycosylated Fc regions using small-angle X-ray scattering
journal, December 2018

Yageta, Seiki; Imamura, Hiroshi; Shibuya, Risa
mAbs, Vol. 11, Issue 3
DOI: 10.1080/19420862.2018.1546086

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Title: Conformational Plasticity of the Immunoglobulin Fc Domain in Solution

Abstract

Citation Formats

Dynamic Views of the Fc Region of Immunoglobulin G Provided by Experimental and Computational Observations journal, July 2019

Dynamic Views of the Fc Region of Immunoglobulin G Provided by Experimental and Computational Observations journal, July 2019

Probing Conformational Diversity of Fc Domains in Aggregation-Prone Monoclonal Antibodies journal, September 2018

C H 2 domain orientation of human immunoglobulin G in solution: Structural comparison of glycosylated and aglycosylated Fc regions using small-angle X-ray scattering journal, December 2018

Dynamic Views of the Fc Region of Immunoglobulin G Provided by Experimental and Computational Observations
journal, July 2019

Dynamic Views of the Fc Region of Immunoglobulin G Provided by Experimental and Computational Observations
journal, July 2019

Probing Conformational Diversity of Fc Domains in Aggregation-Prone Monoclonal Antibodies
journal, September 2018

C _H 2 domain orientation of human immunoglobulin G in solution: Structural comparison of glycosylated and aglycosylated Fc regions using small-angle X-ray scattering
journal, December 2018