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Crystal structure of the first three domains of the type-1 insulin-like growth factor receptor

Abstract

The type-1 insulin-like growth-factor receptor (IGF-1R) and insulin receptor (IR) are closely related members of the tyrosine-kinase receptor superfamily1. IR is essential for glucose homeostasis2, whereas IGF-1R is involved in both normal growth and development and malignant transformation3. Homologues of these receptors are found in animals as simple as cnidarians4. The epidermal growth-factor receptor (EGFR) family is closely related to the IR family and has significant sequence identity to the extracellular portion we describe here. We now present the structure of the first three domains of IGF-1R (L1–Cys-rich–L2) determined to 2.6 Å resolution. The L domains each consist of asingle-stranded right-handed β-helix. The Cys-rich region is composed of eight disulphide-bonded modules, seven of which form a rod-shaped domain with modules associated in an unusual manner. The three domains surround a central space of sufficient size to accommodate a ligand molecule. Although the fragment (residues 1–462) does not bind ligand, many of the determinants responsible for hormone binding and ligand specificity map to this central site. This structure therefore shows how the IR subfamily might interact with their ligands.

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Figure 1: Polypeptide fold for residues 1–459 of IGF-1R.
Figure 2: Amino-acid sequences of IGF-1R and related proteins.
Figure 3: Stereo view of a superposition of the L1 (white) and L2 (black) domains.
Figure 4: Diagram of the association of β-finger motifs.
Figure 5: Surface diagram of the L1 domain of IGF-1R showing the hormone-binding footprint.

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Acknowledgements

Financial support was provided under the Generic Technology component of the Industry Research and Development Act 1986 and from Biota Diabetes Research Pty. We thank P. M. Colman for support and discussions.

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Correspondence to Thomas P. J. Garrett or Colin W. Ward.

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Garrett, T., McKern, N., Lou, M. et al. Crystal structure of the first three domains of the type-1 insulin-like growth factor receptor. Nature 394, 395–399 (1998). https://doi.org/10.1038/28668

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