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Structural Basis for the Regulation of Insulin-like Growth Factors by IGF Binding Proteins

Max Planck Institut für Biochemie, D-82152 Martinsried, Germany.
Structure (Impact Factor: 6.79). 02/2005; 13(1):155-67. DOI: 10.1016/j.str.2004.11.009
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ABSTRACT Insulin-like growth factor binding proteins (IGFBPs) control the extracellular distribution, function, and activity of IGFs. Here, we report an X-ray structure of the binary complex of IGF-I and the N-terminal domain of IGFBP-4 (NBP-4, residues 3-82) and a model of the ternary complex of IGF-I, NBP-4, and the C-terminal domain (CBP-4, residues 151-232) derived from diffraction data with weak definition of the C-terminal domain. These structures show how the IGFBPs regulate IGF signaling. Key features of the structures include (1) a disulphide bond ladder that binds to IGF and partially masks the IGF residues responsible for type 1 IGF receptor (IGF-IR) binding, (2) the high-affinity IGF-I interaction site formed by residues 39-82 in a globular fold, and (3) CBP-4 interactions. Although CBP-4 does not bind individually to either IGF-I or NBP-4, in the ternary complex, CBP-4 contacts both and also blocks the IGF-IR binding region of IGF-I.

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    • "The sites of IGFBP-1 phosphorylation All IGFBPs contain structured N-and C-terminal domains and an unstructured central flexible linker domain. The structures of the N-and C-terminal domains of the IGFBPs have been extensively studied by nuclear magnetic resonance (Sitar et al. 2006; Siwanowicz et al. 2005) mass spectrometry (Neumann and Bach. 1999) and mutation analysis (Imai et al. 2000; Buckway et al. 2001; Yan et al. 2004). "
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    • "Importantly, the role of the IGFBP linker domain in IGF binding remains unclear. A significant proportion of the linker domain can be removed with little effect on overall binding affinity (Qin et al., 1998a) and individual N-and C-domains can bind IGFs with only a ∼10-fold lower affinity compared to intact IGFBPs (Payet et al., 2003; Siwanowicz et al., 2005). Experience from fragment-based drug design shows that linkage of two separate binding entities results in a molecule with a binding affinity that approximates the product of the two individual affinities (Hajduk and Greer, 2007). "
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    • "The three dimensional structure of IGF-1 has been determined by both NMR spectroscopy (Cooke et al., 1991; Sato et al., 1993) and X-ray crystallography method (Brzozowski et al., 2002; Siwanowicz et al., 2005; Vajdos et al., 2001; Zeslawski et al., 2001). The B-and A-domains are similar to those observed in the crystal structure of insulin (Baker et al., 1988; Bentley et al., 1976). "
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