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The Ligands for Human IgG and Their Effector Functions
Open AccessArticle

Dynamic Views of the Fc Region of Immunoglobulin G Provided by Experimental and Computational Observations

1
Exploratory Research Center on Life and Living Systems (ExCELLS) and Institute for Molecular Science (IMS), National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan
2
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan
3
Department of Functional Molecular Science, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Aichi 444-8787, Japan
4
Department of Structural Molecular Science, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Aichi 444-8585, Japan
5
Institute for Integrated Radiation and Nuclear Science, Kyoto University, 2-1010 Asashiro-Nishi, Kumatori, Osaka 590-0494, Japan
6
Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan
7
School of Materials Science, Japan Advanced Institute of Science and Technology (JAIST), 1-1 Asahidai, Nomi 923-1292, Japan
*
Author to whom correspondence should be addressed.
Antibodies 2019, 8(3), 39; https://doi.org/10.3390/antib8030039
Received: 28 April 2019 / Revised: 8 June 2019 / Accepted: 12 June 2019 / Published: 1 July 2019
(This article belongs to the Special Issue Structure and Function of Antibodies)
The Fc portion of immunoglobulin G (IgG) is a horseshoe-shaped homodimer, which interacts with various effector proteins, including Fcγ receptors (FcγRs). These interactions are critically dependent on the pair of N-glycans packed between the two CH2 domains. Fucosylation of these N-glycans negatively affects human IgG1-FcγRIIIa interaction. The IgG1-Fc crystal structures mostly exhibit asymmetric quaternary conformations with divergent orientations of CH2 with respect to CH3. We aimed to provide dynamic views of IgG1-Fc by performing long-timescale molecular dynamics (MD) simulations, which were experimentally validated by small-angle X-ray scattering and nuclear magnetic resonance spectroscopy. Our simulation results indicated that the dynamic conformational ensembles of Fc encompass most of the previously reported crystal structures determined in both free and complex forms, although the major Fc conformers in solution exhibited almost symmetric, stouter quaternary structures, unlike the crystal structures. Furthermore, the MD simulations suggested that the N-glycans restrict the motional freedom of CH2 and endow quaternary-structure plasticity through multiple intramolecular interaction networks. Moreover, the fucosylation of these N-glycans restricts the conformational freedom of the proximal tyrosine residue of functional importance, thereby precluding its interaction with FcγRIIIa. The dynamic views of Fc will provide opportunities to control the IgG interactions for developing therapeutic antibodies. View Full-Text
Keywords: Immunoglobulin G; Fc; conformational dynamics; molecular dynamics simulation; small-angle X-ray scattering; nuclear magnetic resonance; N-glycan; core fucosylation Immunoglobulin G; Fc; conformational dynamics; molecular dynamics simulation; small-angle X-ray scattering; nuclear magnetic resonance; N-glycan; core fucosylation
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Yanaka, S.; Yogo, R.; Inoue, R.; Sugiyama, M.; Itoh, S.G.; Okumura, H.; Miyanoiri, Y.; Yagi, H.; Satoh, T.; Yamaguchi, T.; Kato, K. Dynamic Views of the Fc Region of Immunoglobulin G Provided by Experimental and Computational Observations. Antibodies 2019, 8, 39.

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