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PDBsum entry 4kv5
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Immune system
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PDB id
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4kv5
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References listed in PDB file
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Key reference
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Title
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Structures of a pan-Specific antagonist antibody complexed to different isoforms of tgfβ reveal structural plasticity of antibody-Antigen interactions.
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Authors
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A.Moulin,
M.Mathieu,
C.Lawrence,
R.Bigelow,
M.Levine,
C.Hamel,
J.P.Marquette,
J.Le parc,
C.Loux,
P.Ferrari,
C.Capdevila,
J.Dumas,
B.Dumas,
A.Rak,
J.Bird,
H.Qiu,
C.Q.Pan,
T.Edmunds,
R.R.Wei.
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Ref.
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Protein Sci, 2014,
23,
1698-1707.
[DOI no: ]
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PubMed id
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Abstract
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Various important biological pathways are modulated by TGFβ isoforms; as such
they are potential targets for therapeutic intervention. Fresolimumab, also
known as GC1008, is a pan-TGFβ neutralizing antibody that has been tested
clinically for several indications including an ongoing trial for focal
segmental glomerulosclerosis. The structure of the antigen-binding fragment of
fresolimumab (GC1008 Fab) in complex with TGFβ3 has been reported previously,
but the structural capacity of fresolimumab to accommodate tight interactions
with TGFβ1 and TGFβ2 was insufficiently understood. We report the crystal
structure of the single-chain variable fragment of fresolimumab (GC1008 scFv) in
complex with target TGFβ1 to a resolution of 3.00 Å and the crystal structure
of GC1008 Fab in complex with TGFβ2 to 2.83 Å. The structures provide further
insight into the details of TGFβ recognition by fresolimumab, give a clear
indication of the determinants of fresolimumab pan-specificity and provide
potential starting points for the development of isoform-specific antibodies
using a fresolimumab scaffold.
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