Chemical and structural analysis of an antibody folding intermediate trapped during glycan biosynthesis

Thomas A Bowden, Kavitha Baruah, Charlotte H Coles, David J Harvey, Xiaojie Yu, Byeong-Doo Song, David I Stuart, Alexandru R Aricescu, Christopher N Scanlan, E Yvonne Jones, Max Crispin

Research output: Contribution to journalArticlepeer-review


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 Cγ2 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.
Original languageEnglish
Pages (from-to)17554-63
Number of pages10
JournalJournal of the American Chemical Society
Issue number42
Publication statusPublished - 24 Oct 2012


  • Crystallography, X-Ray
  • Immunoglobulin Fc Fragments
  • Models, Molecular
  • Molecular Structure
  • Polysaccharides
  • Protein Folding

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