3SGK

Unique carbohydrate/carbohydrate interactions are required for high affinity binding of FcgIII and antibodies lacking core fucose

Summary for 3SGK

• Entry DOI: 10.2210/pdb3sgk/pdb
• Related: 3SGJ
• Descriptor: Fc fragment, human Fcg3a receptor, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[2-acetamido-2-deoxy-beta-D-glucopyranose-(1-2)-alpha-D-mannopyranose-(1-6)][2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• Functional Keywords: fc receptor, antibody, afucosylation, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 79022.16

Authors

Ferrara, C.,Grau, S.,Jaeger, C.,Sondermann, P.,Bruenker, P.,Waldhauer, I.,Hennig, M.,Ruf, A.,Rufer, A.C.,Stihle, M.,Umana, P.,Benz, J. (deposition date: 2011-06-15, release date: 2011-08-03, Last modification date: 2020-07-29)

Primary citation

Ferrara, C.,Grau, S.,Jager, C.,Sondermann, P.,Brunker, P.,Waldhauer, I.,Hennig, M.,Ruf, A.,Rufer, A.C.,Stihle, M.,Umana, P.,Benz, J.
Unique carbohydrate-carbohydrate interactions are required for high affinity binding between FcgammaRIII and antibodies lacking core fucose.
Proc.Natl.Acad.Sci.USA, 108:12669-12674, 2011

PubMed Abstract: Antibody-mediated cellular cytotoxicity (ADCC), a key immune effector mechanism, relies on the binding of antigen-antibody complexes to Fcγ receptors expressed on immune cells. Antibodies lacking core fucosylation show a large increase in affinity for FcγRIIIa leading to an improved receptor-mediated effector function. Although afucosylated IgGs exist naturally, a next generation of recombinant therapeutic, glycoenginereed antibodies is currently being developed to exploit this finding. In this study, the crystal structures of a glycosylated Fcγ receptor complexed with either afucosylated or fucosylated Fc were determined allowing a detailed, molecular understanding of the regulatory role of Fc-oligosaccharide core fucosylation in improving ADCC. The structures reveal a unique type of interface consisting of carbohydrate-carbohydrate interactions between glycans of the receptor and the afucosylated Fc. In contrast, in the complex structure with fucosylated Fc, these contacts are weakened or nonexistent, explaining the decreased affinity for the receptor. These findings allow us to understand the higher efficacy of therapeutic antibodies lacking the core fucose and also suggest a unique mechanism by which the immune system can regulate antibody-mediated effector functions.

PubMed: 21768335
DOI: 10.1073/pnas.1108455108

Experimental method

X-RAY DIFFRACTION (2.4 Å)