Document Detail

Structure of the insulin receptor ectodomain reveals a folded-over conformation.
MedLine Citation:
PMID:  16957736     Owner:  NLM     Status:  MEDLINE    
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.
Neil M McKern; Michael C Lawrence; Victor A Streltsov; Mei-Zhen Lou; Timothy E Adams; George O Lovrecz; Thomas C Elleman; Kim M Richards; John D Bentley; Patricia A Pilling; Peter A Hoyne; Kellie A Cartledge; Tam M Pham; Jennifer L Lewis; Sonia E Sankovich; Violet Stoichevska; Elizabeth Da Silva; Christine P Robinson; Maurice J Frenkel; Lindsay G Sparrow; Ross T Fernley; V Chandana Epa; Colin W Ward
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-09-06
Journal Detail:
Title:  Nature     Volume:  443     ISSN:  1476-4687     ISO Abbreviation:  Nature     Publication Date:  2006 Sep 
Date Detail:
Created Date:  2006-09-14     Completed Date:  2006-10-13     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0410462     Medline TA:  Nature     Country:  England    
Other Details:
Languages:  eng     Pagination:  218-21     Citation Subset:  IM    
CSIRO Molecular & Health Technologies, 343 Royal Parade, Parkville, Victoria 3052, Australia.
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MeSH Terms
Crystallography, X-Ray
Immunoglobulin Fab Fragments / immunology
Microscopy, Electron
Models, Molecular
Protein Folding*
Protein Structure, Quaternary
Protein Structure, Tertiary
Receptor, Insulin / chemistry*,  immunology,  metabolism*,  ultrastructure
Reg. No./Substance:
0/Immunoglobulin Fab Fragments; EC, Insulin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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