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

Academic Article
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Overview

authors

  • Bowden, Thomas
  • Baruah, K.
  • Coles, C. H.
  • Harvey, D. J.
  • Yu, X. J.
  • Song, Byeong Doo
  • Stuart, D. I.
  • Aricescu, A. R.
  • Scanlan, C. N.
  • Jones, E. Y.
  • Crispin, Max

publication date

  • October 2012

journal

  • Journal of the American Chemical Society  Journal

abstract

  • 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.

subject areas

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

PubMed Central ID

  • PMC3593610

International Standard Serial Number (ISSN)

  • 0002-7863

Digital Object Identifier (DOI)

  • 10.1021/ja306068g

PubMed ID

  • 23025485
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Additional Document Info

start page

  • 17554

end page

  • 17563

volume

  • 134

issue

  • 42

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