5XJE

Crystal structure of fucosylated IgG1 Fc complexed with bis-glycosylated soluble form of Fc gamma receptor IIIa

Summary for 5XJE

• Entry DOI: 10.2210/pdb5xje/pdb
• Related: 5XJF
• Descriptor: Immunoglobulin gamma-1 heavy chain, Low affinity immunoglobulin gamma Fc region receptor III-A, beta-D-galactopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-2)-alpha-D-mannopyranose-(1-6)-[2-acetamido-2-deoxy-beta-D-glucopyranose-(1-2)-alpha-D-mannopyranose-(1-3)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• Functional Keywords: immune system, complex, fc fragment, igg, receptor, cd16, gamma
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 75076.20

Authors

Sakae, Y.,Satoh, T.,Yagi, H.,Yanaka, S.,Yamaguchi, T.,Isoda, Y.,Iida, S.,Okamoto, Y.,Kato, K. (deposition date: 2017-05-01, release date: 2017-11-01, Last modification date: 2024-10-16)

Primary citation

Sakae, Y.,Satoh, T.,Yagi, H.,Yanaka, S.,Yamaguchi, T.,Isoda, Y.,Iida, S.,Okamoto, Y.,Kato, K.
Conformational effects of N-glycan core fucosylation of immunoglobulin G Fc region on its interaction with Fc gamma receptor IIIa.
Sci Rep, 7:13780-13780, 2017

PubMed Abstract: Antibody-dependent cellular cytotoxicity (ADCC) is promoted through interaction between the Fc region of immunoglobulin G1 (IgG1) and Fcγ receptor IIIa (FcγRIIIa), 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 FcγRIIIa (sFcγRIIIa) in complex with IgG1-Fc. Our simulation highlights increased conformational fluctuation of the N-glycan at Asn162 of sFcγRIIIa 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 sFcγRIIIa 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 sFcγRIIIa without Fc core fucosylation. Our findings offer a structural foundation for designing and developing therapeutic antibodies with improved ADCC activity.

PubMed: 29062024
DOI: 10.1038/s41598-017-13845-8

Experimental method

X-RAY DIFFRACTION (2.4 Å)