Structural analysis of Fc/FcγR complexes: a blueprint for antibody design.
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.
Department of Bioengineering, School of Engineering, The University of Tokyo, Tokyo, Japan.
Jose M M
JM
Caaveiro
Department of Bioengineering, School of Engineering, The University of Tokyo, Tokyo, Japan.|Division of Biological Chemistry and Biologicals, National Institute of Health Sciences, Tokyo, Japan.
Masato
M
Kiyoshi
Department of Bioengineering, School of Engineering, The University of Tokyo, Tokyo, Japan.|Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Kouhei
K
Tsumoto
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000915:Antibody Affinity / Q000276:immunology; D001665:Binding Sites; D014644:Genetic Variation; D006031:Glycosylation; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D007074:Immunoglobulin G / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D008958:Models, Molecular; D011134:Polysaccharides / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D015202:Protein Engineering; D054730:Protein Interaction Domains and Motifs; D017452:Receptors, IgG / Q000737:chemistry* / Q000145:classification / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
D000596:Amino Acids; D000911:Antibodies, Monoclonal; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D011134:Polysaccharides; D017452:Receptors, IgG
X-ray crystallography; biomolecular recognition; immunoglobulin G; immunoglobulin G gamma receptor; protein engineering; therapeutic antibodies