2DSP

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

2DSP の概要

• エントリーDOI: 10.2210/pdb2dsp/pdb
• 関連するPDBエントリー: 1WQJ 2DSQ 2DSR
• 分子名称: Insulin-like growth factor-binding protein 4, Insulin-like growth factor IB (3 entities in total)
• 機能のキーワード: igf, igfbp, insulin, protein binding-hormone-growth factor complex, protein binding/hormone/growth factor
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Secreted: P22692 P05019
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 17490.25

構造登録者

Sitar, T.,Popowicz, G.M.,Siwanowicz, I.,Huber, R.,Holak, T.A. (登録日: 2006-07-05, 公開日: 2006-08-22, 最終更新日: 2024-11-13)

主引用文献

Sitar, T.,Popowicz, G.M.,Siwanowicz, I.,Huber, R.,Holak, T.A.
Structural basis for the inhibition of insulin-like growth factors by insulin-like growth factor-binding proteins.
Proc.Natl.Acad.Sci.Usa, 103:13028-13033, 2006

PubMed Abstract: 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.

PubMed: 16924115
DOI: 10.1073/pnas.0605652103

実験手法

X-RAY DIFFRACTION (2.5 Å)