spacer
spacer

PDBsum entry 3w13

Go to PDB code: 
protein ligands Protein-protein interface(s) links
Hormone receptor/hormone/immune system PDB id
3w13
Jmol
Contents
Protein chains
288 a.a.
116 a.a.
114 a.a.
21 a.a.
15 a.a.
11 a.a.
Ligands
NAG ×2
NAG-NAG-BMA-MAN
NAG-NAG-BMA
PDB id:
3w13
Name: Hormone receptor/hormone/immune system
Title: Insulin receptor ectodomain construct comprising domains l1- complex with high-affinity insulin analogue [d-pro-b26]-dti alphact peptide(693-719) and fab 83-7
Structure: Insulin receptor domains l1-cr. Chain: e. Fragment: unp residues 28-337. Synonym: insulin receptor l1-cr (ir310.T), insulin receptor alpha. Engineered: yes. Monoclonal antibody fab 83-7 fragment - heavy cha chain: c. Engineered: yes.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: insr. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Expression_system_cell_line: lec8 mutant. Expression_system_cell: cho cell. Mus musculus.
Resolution:
4.30Å     R-factor:   0.291     R-free:   0.335
Authors: M.C.Lawrence,B.J.Smith,A.M.Brzozowski
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
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P06213  (INSR_HUMAN) -  Insulin receptor
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1382 a.a.
288 a.a.*
Protein chain
No UniProt id for this chain
Struc: 116 a.a.
Protein chain
No UniProt id for this chain
Struc: 114 a.a.
Protein chain
Pfam   ArchSchema ?
P01308  (INS_HUMAN) -  Insulin
Seq:
Struc:
110 a.a.
21 a.a.
Protein chain
Pfam   ArchSchema ?
P01308  (INS_HUMAN) -  Insulin
Seq:
Struc:
110 a.a.
15 a.a.
Protein chain
Pfam   ArchSchema ?
P06213  (INSR_HUMAN) -  Insulin receptor
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1382 a.a.
11 a.a.
Key:    PfamA domain  Secondary structure
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: Chains E, F: E.C.2.7.10.1  - Receptor protein-tyrosine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate
ATP
+
[protein]-L-tyrosine
Bound ligand (Het Group name = NAG)
matches with 47.62% similarity
= ADP
+ [protein]-L-tyrosine phosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 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  

 

 
    reference    
 
 
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.