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PDBsum entry 2dsq
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Protein binding/hormone/growth factor
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PDB id
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2dsq
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Contents |
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87 a.a.
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49 a.a.
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51 a.a.
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73 a.a.
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58 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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Structural basis for the inhibition of insulin-Like growth factors by insulin-Like growth factor-Binding proteins.
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Authors
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T.Sitar,
G.M.Popowicz,
I.Siwanowicz,
R.Huber,
T.A.Holak.
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Ref.
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Proc Natl Acad Sci U S A, 2006,
103,
13028-13033.
[DOI no: ]
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PubMed id
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Abstract
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Insulin-like growth factor-binding proteins (IGFBPs) control bioavailability,
activity, and distribution of insulin-like growth factor (IGF)1 and -2 through
high-affinity IGFBP/IGF complexes. IGF-binding sites are found on N- and
C-terminal fragments of IGFBPs, the two conserved domains of IGFBPs. The
relative contributions of these domains to IGFBP/IGF complexation has been
difficult to analyze, in part, because of the lack of appropriate
three-dimensional structures. To analyze the effects of N- and C-terminal domain
interactions, we determined several x-ray structures: first, of a ternary
complex of N- and C-terminal domain fragments of IGFBP4 and IGF1 and second, of
a "hybrid" ternary complex using the C-terminal domain fragment of
IGFBP1 instead of IGFBP4. We also solved the binary complex of the N-terminal
domains of IGFBP4 and IGF1, again to analyze C- and N-terminal domain
interactions by comparison with the ternary complexes. The structures reveal the
mechanisms of IGF signaling regulation via IGFBP binding. This finding supports
research into the design of IGFBP variants as therapeutic IGF inhibitors for
diseases of IGF disregulation. In IGFBP4, residues 1-38 form a rigid disulphide
bond ladder-like structure, and the first five N-terminal residues bind to IGF
and partially mask IGF residues responsible for the type 1 IGF receptor binding.
A high-affinity IGF1-binding site is located in a globular structure between
residues 39 and 82. Although the C-terminal domains do not form stable binary
complexes with either IGF1 or the N-terminal domain of IGFBP4, in the ternary
complex, the C-terminal domain contacts both and contributes to blocking of the
IGF1 receptor-binding region of IGF1.
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Figure 3.
Fig. 3. The interaction of IGF1 (green) with NBP4 (residues
3–82) (the yellow surface) and CBP4 (residues 151–232) (the
blue surface). Residues discussed in Results and Discussion are
labeled and shown in stick representation; two hydrogen bonds
from the thumb to IGF1and CBP4 are also shown.
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Figure 4.
Fig. 4. Interaction of the thumb region of NBP4 (residues
3–82) (dark red) and NBP4 (residues 1–92) (dark blue)
complexed to IGF1; IGF1s are in green, with the residues
important for the IGF–IR binding labeled.
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