1RMJ

C-terminal domain of insulin-like growth factor (IGF) binding protein-6: structure and interaction with IGF-II

1RMJ の概要

• エントリーDOI: 10.2210/pdb1rmj/pdb
• NMR情報: BMRB: 5545
• 分子名称: Insulin-like growth factor binding protein 6 (1 entity in total)
• 機能のキーワード: insulin-like growth factor binding protein, hormone-growth factor complex, hormone/growth factor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Secreted: P24592
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 12076.32

構造登録者

Headey, S.J.,Keizer, D.W.,Yao, S.,Brasier, G.,Kantharidis, P.,Bach, L.A.,Norton, R.S. (登録日: 2003-11-28, 公開日: 2004-09-14, 最終更新日: 2024-11-20)

主引用文献

Headey, S.J.,Keizer, D.W.,Yao, S.,Brasier, G.,Kantharidis, P.,Bach, L.A.,Norton, R.S.
C-terminal domain of insulin-like growth factor (IGF) binding protein-6: structure and interaction with IGF-II.
Mol.Endocrinol., 18:2740-2750, 2004

PubMed Abstract: IGFs are important mediators of growth. IGF binding proteins (IGFBPs) 1-6 regulate IGF actions and have IGF-independent actions. The C-terminal domains of IGFBPs contribute to high-affinity IGF binding and modulation of IGF actions and confer some IGF-independent properties, but understanding how they achieve this has been constrained by the lack of a three-dimensional structure. We therefore determined the solution structure of the C-domain of IGFBP-6 using nuclear magnetic resonance (NMR). The domain consists of a thyroglobulin type 1 fold comprising an alpha-helix followed by a loop, a three-stranded antiparallel beta-sheet incorporating a second loop, and finally a disulfide-bonded flexible third loop. The IGF-II binding site on the C-domain was identified by examining NMR spectral changes upon complex formation. It consists of a largely hydrophobic surface patch involving the alpha-helix, the first beta-strand, and the first and second loops. The site was confirmed by mutagenesis of several residues, which resulted in decreased IGF binding affinity. The IGF-II binding site lies adjacent to surfaces likely to be involved in glycosaminoglycan binding of IGFBPs, which might explain their decreased IGF affinity when bound to glycosaminoglycans, and nuclear localization. Our structure provides a framework for understanding the roles of IGFBP C-domains in modulating IGF actions and conferring IGF-independent actions, as well as ultimately for the development of therapeutic IGF inhibitors for diseases including cancer.

PubMed: 15308688
DOI: 10.1210/me.2004-0248

実験手法

SOLUTION NMR