5vu0
From Proteopedia
Crystal structure of the complex between afucosylated/galactosylated human IgG1 Fc and Fc gamma receptor IIIa (CD16A) with Man5 N-glycans
Structural highlights
FunctionIGG1_HUMAN Immunoglobulins, also known as antibodies, are membrane-bound or secreted glycoproteins produced by B lymphocytes. In the recognition phase of humoral immunity, the membrane-bound immunoglobulins serve as receptors which, upon binding of a specific antigen, trigger the clonal expansion and differentiation of B lymphocytes into immunoglobulins-secreting plasma cells. Secreted immunoglobulins mediate the effector phase of humoral immunity, which results in the elimination of bound antigens (PubMed:22158414, PubMed:20176268). The antigen binding site is formed by the variable domain of one heavy chain, together with that of its associated light chain. Thus, each immunoglobulin has two antigen binding sites with remarkable affinity for a particular antigen. The variable domains are assembled by a process called V-(D)-J rearrangement and can then be subjected to somatic hypermutations which, after exposure to antigen and selection, allow affinity maturation for a particular antigen (PubMed:20176268, PubMed:17576170).[1] [2] [3] Publication Abstract from PubMedTherapeutic monoclonal antibodies (mAbs) are largely based on the immunoglobulin G1 (IgG1) scaffold and many elicit a cytotoxic cell-mediated response by binding Fc gamma receptors. Core fucosylation, a prevalent modification to the asparagine(N)-linked carbohydrate on the IgG1 crystallizable fragment (Fc), reduces Fc gamma receptor IIIa (CD16a) binding affinity and mAb efficacy. We determined IgG1 Fc fucosylation reduced CD16a affinity by 1.7 +/- 0.1 kcal/mol when compared to afucosylated IgG1 Fc, however, CD16a N-glycan truncation decreased this penalty by 1.2 +/- 0.1 kcal/mol or 70%. Fc fucosylation restricted the manifold of conformations sampled by displacing the CD16a Asn162-glycan which impinges upon the linkage between the alphamannose(1-6)betamannose residues and promoted contacts with the IgG Tyr296 residue. Fucosylation also impacted IgG1 Fc structure as indicated by changes in resonance frequencies and nuclear spin relaxation observed by solution NMR spectroscopy. The effects of fucosylation on IgG1 Fc may account for the remaining 0.5 +/- 0.1 kcal/mol penalty of fucosylated IgG1 Fc binding CD16a when compared to afucosylated IgG1 Fc. Our results indicated the CD16a Asn162-glycan modulates antibody affinity indirectly through reducing the volume sampled, as opposed to a direct mechanism with intermolecular glycan-glycan contacts previously proposed to stabilize this system. Thus, antibody engineering to enhance intermolecular glycan-glycan contacts will likely provide limited improvement and future designs should maximize affinity by maintaining CD16a Asn162-glycan conformational heterogeneity. Antibody fucosylation lowers FcgammaRIIIa/CD16a affinity by limiting the conformations sampled by the N162-glycan.,Falconer DJ, Subedi GP, Marcella AM, Barb AW ACS Chem Biol. 2018 Jul 17. doi: 10.1021/acschembio.8b00342. PMID:30016589[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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