Antigen binding allosterically promotes Fc receptor recognition

MAbs
Jun ZhaoBuyong Ma

Abstract

A key question in immunology is whether antigen recognition and Fc receptor (FcR) binding are allosterically linked. This question is also relevant for therapeutic antibody design. Antibody Fab and Fc domains are connected by flexible unstructured hinge region. Fc chains have conserved glycosylation sites at Asn297, with each conjugated to a core heptasaccharide and forming biantennary Fc glycan. The glycans modulate the Fc conformations and functions. It is well known that the antibody Fab and Fc domains and glycan affect antibody activity, but whether these elements act independently or synergistically is still uncertain. We simulated four antibody complexes: free antibody, antigen-bound antibody, FcR-bound antibody, and an antigen-antibody-FcR complex. We found that, in the antibody's "T/Y" conformation, the glycans, and the Fc domain all respond to antigen binding, with the antibody population shifting to two dominant clusters, both with the Fc-receptor binding site open. The simulations reveal that the Fc-glycan-receptor complexes also segregate into two conformational clusters, one corresponding to the antigen-free antibody-FcR baseline binding, and the other with an antigen-enhanced antibody-FcR interaction. Our study co...Continue Reading

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Citations

Dec 11, 2019·Antibodies·Mark L ChiuGary L Gilliland
Dec 5, 2019·Frontiers in Oncology·Ruth NussinovHyunbum Jang
Aug 6, 2019·Frontiers in Immunology·Alan L SchmaljohnGeorge K Lewis
Jan 29, 2020·Nature Reviews. Immunology·George V SharonovDmitriy M Chudakov
Dec 19, 2020·Antibodies·Geert van TeteringJeanette Leusen
Feb 11, 2021·The Journal of Physical Chemistry. B·Yashavantha L VishweshwaraiahNikolay V Dokholyan
Mar 1, 2021·Journal of Pharmaceutical Sciences·Juan P Rincon PabonDavid D Weis
Mar 20, 2021·Frontiers in Immunology·Monica L Fernández-QuinteroKlaus R Liedl
May 26, 2021·MAbs·Monica L Fernández-QuinteroKlaus R Liedl
Jun 3, 2021·International Journal of Molecular Sciences·Christian W KellerJan D Lünemann
Aug 28, 2021·Frontiers in Immunology·Monica L Fernández-QuinteroKlaus R Liedl
Oct 29, 2021·Biophysical Journal·Simona SaporitiIvano Eberini

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Methods Mentioned

BETA
glycosylation
electron tomography
NMR

Software Mentioned

NAMD
PROTMAP2D
NetworkView
CHARMM
GUI
SWISS
VMD
MODEL

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