PMID:16957736

Citation	McKern, NM, Lawrence, MC, Streltsov, VA, Lou, MZ, Adams, TE, Lovrecz, GO, Elleman, TC, Richards, KM, Bentley, JD, Pilling, PA, Hoyne, PA, Cartledge, KA, Pham, TM, Lewis, JL, Sankovich, SE, Stoichevska, V, Da Silva, E, Robinson, CP, Frenkel, MJ, Sparrow, LG, Fernley, RT, Epa, VC and Ward, CW (2006) Structure of the insulin receptor ectodomain reveals a folded-over conformation. Nature 443:218-21
Abstract	The insulin receptor is a phylogenetically ancient tyrosine kinase receptor found in organisms as primitive as cnidarians and insects. In higher organisms it is essential for glucose homeostasis, whereas the closely related insulin-like growth factor receptor (IGF-1R) is involved in normal growth and development. The insulin receptor is expressed in two isoforms, IR-A and IR-B; the former also functions as a high-affinity receptor for IGF-II and is implicated, along with IGF-1R, in malignant transformation. Here we present the crystal structure at 3.8 A resolution of the IR-A ectodomain dimer, complexed with four Fabs from the monoclonal antibodies 83-7 and 83-14 (ref. 4), grown in the presence of a fragment of an insulin mimetic peptide. The structure reveals the domain arrangement in the disulphide-linked ectodomain dimer, showing that the insulin receptor adopts a folded-over conformation that places the ligand-binding regions in juxtaposition. This arrangement is very different from previous models. It shows that the two L1 domains are on opposite sides of the dimer, too far apart to allow insulin to bind both L1 domains simultaneously as previously proposed. Instead, the structure implicates the carboxy-terminal surface of the first fibronectin type III domain as the second binding site involved in high-affinity binding.
Links	PubMed Online version:10.1038/nature05106
Keywords	Crystallography, X-Ray; Dimerization; Immunoglobulin Fab Fragments/immunology; Microscopy, Electron; Models, Molecular; Protein Folding; Protein Structure, Quaternary; Protein Structure, Tertiary; Receptor, Insulin/chemistry; Receptor, Insulin/immunology; Receptor, Insulin/metabolism; Receptor, Insulin/ultrastructure
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:INSR	enables	GO:0042802: identical protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:P06213-1	F		Seeded From UniProt	complete

References

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