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Structural analysis of Fc/FcγR complexes: a blueprint for antibody design
Author(s) -
Caaveiro Jose M. M.,
Kiyoshi Masato,
Tsumoto Kouhei
Publication year - 2015
Publication title -
immunological reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.839
H-Index - 223
eISSN - 1600-065X
pISSN - 0105-2896
DOI - 10.1111/imr.12365
Subject(s) - fragment crystallizable region , antibody , receptor , effector , glycan , biology , immunoglobulin fc fragments , fc receptor , immunoglobulin g , complementarity determining region , immune system , immunology , microbiology and biotechnology , chemistry , glycoprotein , computational biology , biochemistry , monoclonal antibody
Summary The number of studies and the quality of the structural data of Fcγ receptors (FcγRs) has rapidly increased in the last few years. Upon critical examination of the literature, we have extracted general conclusions that could explain differences in affinity and selectivity of FcγRs for immunoglobulin G (IgG) based on structural considerations. FcγRs employ a little conserved asymmetric surface of domain D2 composed of two distinct subsites to recognize the well‐conserved lower hinge region of IgG1‐Fc. The extent of the contact interface with the antibody in subsite 1 of the receptor (but not in subsite 2), the geometrical complementarity between antibody and receptor, and the number of polar interactions contribute decisively toward strengthening the binding affinity of the antibody for the receptor. In addition, the uncertain role of the N‐linked glycan of IgG for the binding and effector responses elicited by FcγRs is discussed. The available data suggest that not only the non‐covalent interactions between IgG and FcγRs but also their dynamic features are essential for the immune response elicited through these receptors. We believe that the integration of structural, thermodynamic, and kinetic data will be critical for the design and validation of the next generation of therapeutic antibodies with enhanced effector capabilities.