5xje
From Proteopedia
Crystal structure of fucosylated IgG1 Fc complexed with bis-glycosylated soluble form of Fc gamma receptor IIIa
Structural highlights
DiseaseFCG3A_HUMAN The disease is caused by mutations affecting the gene represented in this entry.[1] [2] [3] [4] FunctionFCG3A_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 promoted through interaction between the Fc region of immunoglobulin G1 (IgG1) and Fcgamma receptor IIIa (FcgammaRIIIa), depending on N-glycosylation of these glycoproteins. In particular, core fucosylation of IgG1-Fc N-glycans negatively affects this interaction and thereby compromises ADCC activity. To address the mechanisms of this effect, we performed replica-exchange molecular dynamics simulations based on crystallographic analysis of a soluble form of FcgammaRIIIa (sFcgammaRIIIa) in complex with IgG1-Fc. Our simulation highlights increased conformational fluctuation of the N-glycan at Asn162 of sFcgammaRIIIa upon fucosylation of IgG1-Fc, consistent with crystallographic data giving no interpretable electron density for this N-glycan, except for the innermost part. The fucose residue disrupts optimum intermolecular carbohydrate-carbohydrate interactions, rendering this sFcgammaRIIIa glycan distal from the Fc glycan. Moreover, our simulation demonstrates that core fucosylation of IgG1-Fc affects conformational dynamics and rearrangements of surrounding amino acid residues, typified by Tyr296 of IgG1-Fc, which was more extensively involved in the interaction with sFcgammaRIIIa without Fc core fucosylation. Our findings offer a structural foundation for designing and developing therapeutic antibodies with improved ADCC activity. Conformational effects of N-glycan core fucosylation of immunoglobulin G Fc region on its interaction with Fcgamma receptor IIIa.,Sakae Y, Satoh T, Yagi H, Yanaka S, Yamaguchi T, Isoda Y, Iida S, Okamoto Y, Kato K Sci Rep. 2017 Oct 23;7(1):13780. doi: 10.1038/s41598-017-13845-8. PMID:29062024[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Homo sapiens | Large Structures | Iida S | Isoda Y | Kato K | Okamoto Y | Sakae Y | Satoh T | Yagi H | Yamaguchi T | Yanaka S
