期刊
ANTIBODIES
卷 8, 期 3, 页码 -出版社
MDPI
DOI: 10.3390/antib8030039
关键词
Immunoglobulin G; Fc; conformational dynamics; molecular dynamics simulation; small-angle X-ray scattering; nuclear magnetic resonance; N-glycan; core fucosylation
类别
资金
- Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan [JP17H06414, JP17H05893, JP18K14892, JP18H05203, JP19H01017, JP19J15602, JP17K07361, JP18H05229, JP18H03681]
- Cooperative Research Program of Institute for Protein Research, Osaka University [NMRCR-16-05, NMRCR-17-05, NMRCR-18-05]
- Exploratory Research Center on Life and Living Systems (ExCELLS) [18-301]
- project for Construction of the basis for the advanced materials science and analytical study by the innovative use of quantum beam and nuclear sciences in Institute for Integrated Radiation and Nuclear Science, Kyoto University
The Fc portion of immunoglobulin G (IgG) is a horseshoe-shaped homodimer, which interacts with various effector proteins, including Fc gamma receptors (Fc gamma Rs). These interactions are critically dependent on the pair of N-glycans packed between the two C(H)2 domains. Fucosylation of these N-glycans negatively affects human IgG1-Fc gamma RIIIa interaction. The IgG1-Fc crystal structures mostly exhibit asymmetric quaternary conformations with divergent orientations of C(H)2 with respect to C(H)3. 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 C(H)2 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 Fc gamma RIIIa. The dynamic views of Fc will provide opportunities to control the IgG interactions for developing therapeutic antibodies.
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