5GSQ

Crystal structure of IgG Fc with a homogeneous glycoform and Antibody-Dependent Cellular Cytotoxicity

Summary for 5GSQ

• Entry DOI: 10.2210/pdb5gsq/pdb
• Descriptor: Ig gamma-1 chain C region, beta-D-galactopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-2)-alpha-D-mannopyranose-(1-6)-[alpha-D-mannopyranose-(1-3)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, N-acetyl-alpha-neuraminic acid-(2-6)-beta-D-galactopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-2)-alpha-D-mannopyranose-(1-6)-[alpha-D-mannopyranose-(1-3)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: antibody fc, homogeneous n-glycan, enhanced adcc, di-sialylation, immune system
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 106418.35

Authors

Chen, C.-L.,Hsu, J.-C.,Lin, C.-W.,Wu, C.-Y.,Wong, C.-H.,Ma, C. (deposition date: 2016-08-17, release date: 2017-06-28, Last modification date: 2023-11-08)

Primary citation

Chen, C.-L.,Hsu, J.-C.,Lin, C.-W.,Wang, C.-H.,Tsai, M.-H.,Wu, C.-Y.,Wong, C.-H.,Ma, C.
Crystal Structure of a Homogeneous IgG-Fc Glycoform with the N-Glycan Designed to Maximize the Antibody Dependent Cellular Cytotoxicity
ACS Chem. Biol., 12:1335-1345, 2017

PubMed Abstract: N-glycosylation on IgG modulates Fc conformation and effector functions. An IgG-Fc contains a human sialo-complex type (hSCT) glycan of biantennary structure with two α2,6-sialylations and without core-fucosylation is an optimized glycoform developed to enhance the antibody dependent cellular cytotoxicity (ADCC). hSCT modification not only enhances the binding affinity to Fc receptors in the presence of antigen but also in some cases provides gain-of-function effector activity. We used enzymatic glyco-engineering to prepare an IgG-Fc with homogeneous hSCT attached to each C2 domain and solved its crystal structure. A compact form and an open form were observed in an asymmetric unit in the crystal. In the compact structure, the double glycan latches from the two hSCT chains stabilize the C2 domains in a closed conformation. In the open structure, the terminal sialic acid (N-acetylneuraminic acid or NeuNAc) residue interacts through water-mediated hydrogen bonds with the D249-L251 helix, to modulate the pivot region of the C2-C3 interface. The double glycan latches and the sialic acid modulation may be mutually exclusive. This is the first crystal structure of glyco-engineered Fc with enhanced effector activities. This work provides insights into the relationship between the structural stability and effector functions affected by hSCT modification and the development of better antibodies for therapeutic applications.

PubMed: 28318221
DOI: 10.1021/acschembio.7b00140

Experimental method

X-RAY DIFFRACTION (1.85 Å)