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Chemical and Structural Analysis of an Antibody Folding Intermediate Trapped during Glycan Biosynthesis
DOI:
10.1021/ja306068g
PMID:
23025485
Authors:
Thomas A.
Bowden
(Division of Structural Biology, University of Oxford)
,
Kavitha
Baruah
(University of Oxford)
,
Charlotte H.
Coles
(Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford)
,
David J.
Harvey
(Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford)
,
Xiaojie
Yu
(Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford)
,
Byeong-doo
Song
(Scripps Korea Antibody Institute)
,
Dave
Stuart
(Diamond Light Source)
,
A Radu
Aricescu
(Division of Structural Biology, University of Oxford, Wellcome Trust Centre for Human Genetics)
,
Christopher N.
Scanlan
(Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford)
,
E. Yvonne
Jones
(University of Oxford)
,
Max
Crispin
(Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford)
Co-authored by industrial partner:
No
Type:
Journal Paper
Journal:
Journal Of The American Chemical Society
, VOL 134 (42)
, PAGES 5723-5729
State:
Published (Approved)
Published:
October 2012

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 C?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.
Subject Areas:
Biology and Bio-materials
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