Document Detail


Structure of the insulin receptor ectodomain reveals a folded-over conformation.
MedLine Citation:
PMID:  16957736     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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
Related Documents :
7588336 - Regulation of insulin-like growth factor (igf) binding protein-3 phosphorylation by igf-i.
3901776 - Insulin binding and glucose transport in rat skeletal muscle sarcolemmal vesicles.
9348216 - Insulin-like growth factor binding protein-2 binds to cell surface proteoglycans in the...
6242266 - Insulin processing. its correlation with glucose conversion to co2.
11688136 - Ellipticine analogues and related compounds as inhibitors of reverse transcriptase and ...
17760566 - Mislocalization of human transcription factor mok2 in the presence of pathogenic mutati...
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    
Affiliation:
CSIRO Molecular & Health Technologies, 343 Royal Parade, Parkville, Victoria 3052, Australia.
Data Bank Information
Bank Name/Acc. No.:
PDB/2DTG
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Crystallography, X-Ray
Dimerization
Immunoglobulin Fab Fragments / immunology
Microscopy, Electron
Models, Molecular
Protein Folding*
Protein Structure, Quaternary
Protein Structure, Tertiary
Receptor, Insulin / chemistry*,  immunology,  metabolism*,  ultrastructure
Chemical
Reg. No./Substance:
0/Immunoglobulin Fab Fragments; EC 2.7.10.1/Receptor, Insulin

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


Previous Document:  Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a.
Next Document:  p16INK4a induces an age-dependent decline in islet regenerative potential.