2dsq
Structural Basis for the Inhibition of Insulin-like Growth Factors by IGF Binding Proteins
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OverviewOverview
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.
DiseaseDisease
Known disease associated with this structure: Growth retardation with deafness and mental retardation due to IGF1 deficiency OMIM:[147440]
About this StructureAbout this Structure
2DSQ is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Structural basis for the inhibition of insulin-like growth factors by insulin-like growth factor-binding proteins., Sitar T, Popowicz GM, Siwanowicz I, Huber R, Holak TA, Proc Natl Acad Sci U S A. 2006 Aug 29;103(35):13028-33. Epub 2006 Aug 21. PMID:16924115
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