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PDBsum entry 3w14

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protein Protein-protein interface(s) links
Hormone/hormone receptor/immune system PDB id
3w14
Jmol
Contents
Protein chains
21 a.a.
17 a.a.
193 a.a.
214 a.a.
580 a.a.
PDB id:
3w14
Name: Hormone/hormone receptor/immune system
Title: Insulin receptor ectodomain construct comprising domains l1, fniii-1 and alphact peptide in complex with bovine insulin 83-14
Structure: Insulin a chain. Chain: a, i. Insulin b chain. Chain: b, j. Monoclonal antibody fab 83-14 - heavy chain. Chain: c, p. Engineered: yes. Monoclonal antibody fab 83-14 - light chain. Chain: d, q.
Source: Bos taurus. Bovine. Organism_taxid: 9913. Mus musculus. Mouse. Organism_taxid: 10090. Expressed in: mus musculus. Expression_system_taxid: 10090. Expression_system_cell: hybridoma cell.
Resolution:
4.40Å     R-factor:   0.246     R-free:   0.262
Authors: M.C.Lawrence,B.J.Smith
Key ref: J.G.Menting et al. (2013). How insulin engages its primary binding site on the insulin receptor. Nature, 493, 241-245. PubMed id: 23302862
Date:
06-Nov-12     Release date:   09-Jan-13    
PROCHECK
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 Headers
 References

Protein chains
Pfam   ArchSchema ?
P01317  (INS_BOVIN) -  Insulin
Seq:
Struc:
105 a.a.
21 a.a.
Protein chains
Pfam   ArchSchema ?
P01317  (INS_BOVIN) -  Insulin
Seq:
Struc:
105 a.a.
17 a.a.
Protein chains
No UniProt id for this chain
Struc: 193 a.a.
Protein chains
No UniProt id for this chain
Struc: 214 a.a.
Protein chains
Pfam   ArchSchema ?
P06213  (INSR_HUMAN) -  Insulin receptor
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1382 a.a.
580 a.a.*
Key:    PfamA domain  Secondary structure
* PDB and UniProt seqs differ at 12 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   2 terms 
  Biological process     transmembrane receptor protein tyrosine kinase signaling pathway   2 terms 
  Biochemical function     hormone activity     3 terms  

 

 
Nature 493:241-245 (2013)
PubMed id: 23302862  
 
 
How insulin engages its primary binding site on the insulin receptor.
J.G.Menting, J.Whittaker, M.B.Margetts, L.J.Whittaker, G.K.Kong, B.J.Smith, C.J.Watson, L.Záková, E.Kletvíková, J.Jiráček, S.J.Chan, D.F.Steiner, G.G.Dodson, A.M.Brzozowski, M.A.Weiss, C.W.Ward, M.C.Lawrence.
 
  ABSTRACT  
 
Insulin receptor signalling has a central role in mammalian biology, regulating cellular metabolism, growth, division, differentiation and survival. Insulin resistance contributes to the pathogenesis of type 2 diabetes mellitus and the onset of Alzheimer's disease; aberrant signalling occurs in diverse cancers, exacerbated by cross-talk with the homologous type 1 insulin-like growth factor receptor (IGF1R). Despite more than three decades of investigation, the three-dimensional structure of the insulin-insulin receptor complex has proved elusive, confounded by the complexity of producing the receptor protein. Here we present the first view, to our knowledge, of the interaction of insulin with its primary binding site on the insulin receptor, on the basis of four crystal structures of insulin bound to truncated insulin receptor constructs. The direct interaction of insulin with the first leucine-rich-repeat domain (L1) of insulin receptor is seen to be sparse, the hormone instead engaging the insulin receptor carboxy-terminal α-chain (αCT) segment, which is itself remodelled on the face of L1 upon insulin binding. Contact between insulin and L1 is restricted to insulin B-chain residues. The αCT segment displaces the B-chain C-terminal β-strand away from the hormone core, revealing the mechanism of a long-proposed conformational switch in insulin upon receptor engagement. This mode of hormone-receptor recognition is novel within the broader family of receptor tyrosine kinases. We support these findings by photo-crosslinking data that place the suggested interactions into the context of the holoreceptor and by isothermal titration calorimetry data that dissect the hormone-insulin receptor interface. Together, our findings provide an explanation for a wealth of biochemical data from the insulin receptor and IGF1R systems relevant to the design of therapeutic insulin analogues.