Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 134, Issue 42, Pages 17554-17563Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ja306068g
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Funding
- University College, Oxford [089026/Z/09/Z]
- Oxford Glycobiology Institute
- MRC
- Wellcome Trust, International AIDS Vaccine Initiative
- European Commission [FP6-RTD-031220]
- Scripps Korea Antibody Institute
- Wellcome Trust [089026/Z/09/Z] Funding Source: Wellcome Trust
- MRC [G9900061, G0700232, G0900084] Funding Source: UKRI
- Medical Research Council [G0900084, G1100525, G0700232, G9900061] Funding Source: researchfish
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Human IgG Fc glycosylation modulates immunological effector functions such as antibody-dependent cellular cytotoxicity and phagocytosis. Engineering of Fc glycans therefore enables fine-tuning of the therapeutic properties of monoclonal antibodies. The N-linked glycans of Fc are typically complex-type, forming a network of noncovalent interactions along the protein surface of the C gamma 2 domain. Here, we manipulate the mammalian glycan-processing pathway to trap IgG1 Fc at sequential stages of maturation, from oligomannose- to hybrid- to complex type glycans, and show that the Fc is structurally stabilized following the transition of glycans from their hybrid- to complex type state. X-ray crystallographic analysis of this hybrid type intermediate reveals that N-linked glycans undergo conformational changes upon maturation, including a flip within the trimannosyl core. Our crystal structure of this intermediate reveals a molecular basis for antibody biogenesis and provides a template for the structure guided engineering of the protein-glycan interface of therapeutic antibodies.
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