5bw7
From Proteopedia
Crystal structure of nonfucosylated Fc Y296W mutant complexed with bis-glycosylated soluble form of Fc gamma receptor IIIa
Structural highlights
Disease[IGHG1_HUMAN] Defects in IGHG1 are a cause of multiple myeloma (MM) [MIM:254500]. MM is a malignant tumor of plasma cells usually arising in the bone marrow and characterized by diffuse involvement of the skeletal system, hyperglobulinemia, Bence-Jones proteinuria and anemia. Complications of multiple myeloma are bone pain, hypercalcemia, renal failure and spinal cord compression. The aberrant antibodies that are produced lead to impaired humoral immunity and patients have a high prevalence of infection. Amyloidosis may develop in some patients. Multiple myeloma is part of a spectrum of diseases ranging from monoclonal gammopathy of unknown significance (MGUS) to plasma cell leukemia. Note=A chromosomal aberration involving IGHG1 is found in multiple myeloma. Translocation t(11;14)(q13;q32) with the IgH locus. Translocation t(11;14)(q13;q32) with CCND1; translocation t(4;14)(p16.3;q32.3) with FGFR3; translocation t(6;14)(p25;q32) with IRF4. [FCG3A_HUMAN] The disease is caused by mutations affecting the gene represented in this entry.[1] [2] [3] [4] Function[FCG3A_HUMAN] Receptor for the Fc region of IgG. Binds complexed or aggregated IgG and also monomeric IgG. Mediates antibody-dependent cellular cytotoxicity (ADCC) and other antibody-dependent responses, such as phagocytosis.[5] [6] Publication Abstract from PubMedAntibody-dependent cellular cytotoxicity (ADCC) is an important effector function determining the clinical efficacy of therapeutic antibodies. Core fucose removal from N-glycans on the Fc portion of immunoglobulin G (IgG) improves the binding affinity for Fcgamma receptor IIIa (FcgammaRIIIa) and dramatically enhances ADCC. Our previous structural analyses revealed that Tyr-296 of IgG1-Fc plays a critical role in the interaction with FcgammaRIIIa, particularly in the enhanced FcgammaRIIIa binding of nonfucosylated IgG1. However, the importance of the Tyr-296 residue in the antibody in the interaction with various Fcgamma receptors has not yet been elucidated. To further clarify the biological importance of this residue, we established comprehensive Tyr-296 mutants as fucosylated and nonfucosylated anti-CD20 IgG1s rituximab variants and examined their binding to recombinant soluble human Fcgamma receptors: shFcgammaRI, shFcgammaRIIa, shFcgammaRIIIa, and shFcgammaRIIIb. Some of the mutations affected the binding of antibody to not only shFcgammaRIIIa but also shFcgammaRIIa and shFcgammaRIIIb, suggesting that the Tyr-296 residue in the antibody was also involved in interactions with FcgammaRIIa and FcgammaRIIIb. For FcgammaRIIIa binding, almost all Tyr-296 variants showed lower binding affinities than the wild-type antibody, irrespective of their core fucosylation, particularly in Y296K and Y296P. Notably, only the Y296W mutant showed improved binding to FcgammaRIIIa. The 3.00 A-resolution crystal structure of the nonfucosylated Y296W mutant in complex with shFcgammaRIIIa harboring two N-glycans revealed that the Tyr-to-Trp substitution increased the number of potential contact atoms in the complex, thus improving the binding of the antibody to shFcgammaRIIIa. The nonfucosylated Y296W mutant retained high ADCC activity, relative to the nonfucosylated wild-type IgG1, and showed greater binding affinity for FcgammaRIIa. Our data may improve our understanding of the biological importance of human IgG1-Fc Tyr-296 in interactions with various Fcgamma receptors, and have applications in the modulation of the IgG1-Fc function of therapeutic antibodies. Importance of the Side Chain at Position 296 of Antibody Fc in Interactions with FcgammaRIIIa and Other Fcgamma Receptors.,Isoda Y, Yagi H, Satoh T, Shibata-Koyama M, Masuda K, Satoh M, Kato K, Iida S PLoS One. 2015 Oct 7;10(10):e0140120. doi: 10.1371/journal.pone.0140120., eCollection 2015. PMID:26444434[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Human | Large Structures | Iida, S | Isoda, Y | Kato, K | Masuda, K | Satoh, M | Satoh, T | Shibata-Koyama, M | Yagi, H | Cd16 | Complex | Fc fragment | Gamma | Igg | Immune system | Receptor
