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PDBsum entry 3eo1
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Immune system/cytokine
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PDB id
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3eo1
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Contents |
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215 a.a.
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216 a.a.
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112 a.a.
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References listed in PDB file
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Key reference
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Title
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A cytokine-Neutralizing antibody as a structural mimetic of 2 receptor interactions.
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Authors
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C.Grütter,
T.Wilkinson,
R.Turner,
S.Podichetty,
D.Finch,
M.Mccourt,
S.Loning,
L.Jermutus,
M.G.Grütter.
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Ref.
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Proc Natl Acad Sci U S A, 2008,
105,
20251-20256.
[DOI no: ]
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PubMed id
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Abstract
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TGF-beta isoforms are key modulators of a broad range of biological pathways and
increasingly are exploited as therapeutic targets. Here, we describe the crystal
structures of a pan-TGF-beta neutralizing antibody, GC-1008, alone and in
complex with TGF-beta3. The antibody is currently in clinical evaluation for
idiopathic pulmonary fibrosis, melanoma, and renal cell cancer. GC-1008
recognizes an asymmetric binding interface across the TGF-beta homodimer with
high affinity. Whereas both cognate receptors, TGF-beta-receptor types I and II,
are required to recognize all 3 TGF-beta isoforms, GC-1008 has been engineered
to bind with high affinity to TGF-beta1, 2, and 3 via a single interaction
surface. Comparison with existing structures and models of TGF-beta interaction
with its receptors suggests that the antibody binds to a similar epitope to the
2 receptors together and is therefore a structurally different but functionally
identical mimic of the binding mode of both receptors.
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Figure 2.
GC-1008–TGF-β3 binding interface. (A) Surface
representation of the complex. The main binding interactions of
the Fab fragments toward the TGF-β3 homodimer are accomplished
by CDR loops of the heavy chains (yellow). (B) Contact residues
of GC-1008 (gray) involved in the recognition of TGF-β3. The
TGF-β3 homodimer is shown as transparent surface representation.
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Figure 4.
Comparison of the GC-1008 binding mode with type I and type
II TGF-β receptor binding. (A) Structure of the ternary TGF-β
signaling complex consisting of TGF-β3 bound to its type I and
II receptors. Structure is shown as depicted in ref. 14. (B)
Schematic comparison of GC-1008 binding versus receptor binding.
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