PDBsum entry 1p14

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protein links
Transferase PDB id
Protein chain
287 a.a. *
Waters ×188
* Residue conservation analysis
PDB id:
Name: Transferase
Title: Crystal structure of a catalytic-loop mutant of the insulin receptor tyrosine kinase
Structure: Insulin receptor. Chain: a. Fragment: tyrosine kinase domain, residues 978-1283. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.
1.90Å     R-factor:   0.224     R-free:   0.240
Authors: S.Li,N.D.Covino,E.G.Stein,J.H.Till,S.R.Hubbard
Key ref:
S.Li et al. (2003). Structural and biochemical evidence for an autoinhibitory role for tyrosine 984 in the juxtamembrane region of the insulin receptor. J Biol Chem, 278, 26007-26014. PubMed id: 12707268 DOI: 10.1074/jbc.M302425200
11-Apr-03     Release date:   22-Jul-03    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P06213  (INSR_HUMAN) -  Insulin receptor
1382 a.a.
287 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.  - Receptor protein-tyrosine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate
+ [protein]-L-tyrosine
+ [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     membrane   1 term 
  Biological process     transmembrane receptor protein tyrosine kinase signaling pathway   2 terms 
  Biochemical function     transferase activity, transferring phosphorus-containing groups     4 terms  


DOI no: 10.1074/jbc.M302425200 J Biol Chem 278:26007-26014 (2003)
PubMed id: 12707268  
Structural and biochemical evidence for an autoinhibitory role for tyrosine 984 in the juxtamembrane region of the insulin receptor.
S.Li, N.D.Covino, E.G.Stein, J.H.Till, S.R.Hubbard.
Tyrosine 984 in the juxtamembrane region of the insulin receptor, between the transmembrane helix and the cytoplasmic tyrosine kinase domain, is conserved among all insulin receptor-like proteins from hydra to humans. Crystallographic studies of the tyrosine kinase domain and proximal juxtamembrane region reveal that Tyr-984 interacts with several other conserved residues in the N-terminal lobe of the kinase domain, stabilizing a catalytically nonproductive position of alpha-helix C. Steady-state kinetics measurements on the soluble kinase domain demonstrate that replacement of Tyr-984 with phenylalanine results in a 4-fold increase in kcat in the unphosphorylated (basal state) enzyme. Moreover, mutation of Tyr-984 in the full-length insulin receptor results in significantly elevated receptor phosphorylation levels in cells, both in the absence of insulin and following insulin stimulation. These data demonstrate that Tyr-984 plays an important structural role in maintaining the quiescent, basal state of the insulin receptor. In addition, the structural studies suggest a possible target site for small molecule activators of the insulin receptor, with potential use in the treatment of noninsulin-dependent diabetes mellitus.
  Selected figure(s)  
Figure 2.
FIG. 2. Crystal structure of IRKD1132N. A, 2F[o] - F[c] electron density map (1.9 Å resolution, 1 contour) is shown in wire mesh (purple) in the region of Tyr-984. The superimposed refined structure of IRKD1132N is shown in stick representation, with the proximal juxtamembrane region (residues 978-988) colored orange, residues in C colored yellow, and residues in the sheet (and connecting loops) colored cyan. Ordered water molecules are indicated with red spheres. Selected residues are labeled. B, ribbon diagram of the IRKD1132N structure. strands are colored cyan, and -helices are colored yellow. The proximal juxtamembrane region including Tyr-984 is colored orange, with the side chain of Tyr-984 shown in ball-and-stick representation, and C in the N-terminal lobe is labeled. The dashed gray line indicates that the activation loop is disordered (from Met-1153 through Leu-1171). The N and C termini are denoted by N and C.
Figure 3.
FIG. 3. Conformation of the proximal juxtamembrane region in IRK. Stereo views of the proximal juxtamembrane region and the N-terminal kinase lobe from the IRKD1132N structure (A) and the tris-phosphorylated IRKY984F structure (13) (B) are shown. The view is from above with respect to the view in Fig. 3. The juxtamembrane region is shown in ball-and-stick representation with carbon atoms colored orange, nitrogen atoms colored blue, and oxygen atoms colored red. The side chains of selected residues of the N-terminal kinase lobe are shown in ball- and-stick representation with carbon atoms colored gray, nitrogen atoms colored blue, and oxygen atoms colored red. Semi-transparent van der Waals' surfaces in A indicate hydrophobic packing of Tyr-984 with Leu-1045 and Val-1065. C, schematic diagram (approximate spatial layout) showing the invariant residues in the insulin receptor subfamily that form the Tyr-984 binding pocket. The residue labels are placed alongside the C atoms of the side chains. The backbone nitrogen atoms of Trp-989 and Ser-1067 are included as well as the carbonyl oxygen of nonconserved Val-985 (dark gray). Hydrogen bonds are depicted by dashed lines, and van der Waals' interactions (<3.8 Å) with Tyr-984 are depicted as concentric half-circles.
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2003, 278, 26007-26014) copyright 2003.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20095048 H.M.Zhang, X.Yu, M.J.Greig, K.S.Gajiwala, J.C.Wu, W.Diehl, E.A.Lunney, M.R.Emmett, and A.G.Marshall (2010).
Drug binding and resistance mechanism of KIT tyrosine kinase revealed by hydrogen/deuterium exchange FTICR mass spectrometry.
  Protein Sci, 19, 703-715.  
20810646 W.W.Chen, M.Niepel, and P.K.Sorger (2010).
Classic and contemporary approaches to modeling biochemical reactions.
  Genes Dev, 24, 1861-1875.  
18971950 A.Chase, B.Schultheis, S.Kreil, J.Baxter, C.Hidalgo-Curtis, A.Jones, L.Zhang, F.H.Grand, J.V.Melo, and N.C.Cross (2009).
Imatinib sensitivity as a consequence of a CSF1R-Y571D mutation and CSF1/CSF1R signaling abnormalities in the cell line GDM1.
  Leukemia, 23, 358-364.  
19274663 C.W.Ward, and M.C.Lawrence (2009).
Ligand-induced activation of the insulin receptor: a multi-step process involving structural changes in both the ligand and the receptor.
  Bioessays, 31, 422-434.  
19642985 H.J.Tsai, and S.Y.Chou (2009).
A novel hydroxyfuroic acid compound as an insulin receptor activator structure and activity relationship of a prenylindole moiety to insulin receptor activation.
  J Biomed Sci, 16, 68.  
19497423 R.V.Rajala, and A.Rajala (2009).
Cytoskeletal components enhance the autophosphorylation of retinal insulin receptor.
  Chem Biol Interact, 180, 245-253.  
18278056 J.Wu, Y.D.Tseng, C.F.Xu, T.A.Neubert, M.F.White, and S.R.Hubbard (2008).
Structural and biochemical characterization of the KRLB region in insulin receptor substrate-2.
  Nat Struct Mol Biol, 15, 251-258.
PDB codes: 3bu3 3bu5 3bu6
17586502 B.P.Craddock, C.Cotter, and W.T.Miller (2007).
Autoinhibition of the insulin-like growth factor I receptor by the juxtamembrane region.
  FEBS Lett, 581, 3235-3240.  
16091740 J.Ishiko, M.Mizuki, I.Matsumura, H.Shibayama, H.Sugahara, G.Scholz, H.Serve, and Y.Kanakura (2005).
Roles of tyrosine residues 845, 892 and 922 in constitutive activation of murine FLT3 kinase domain mutant.
  Oncogene, 24, 8144-8153.  
16271887 S.Li, R.S.Depetris, D.Barford, J.Chernoff, and S.R.Hubbard (2005).
Crystal structure of a complex between protein tyrosine phosphatase 1B and the insulin receptor tyrosine kinase.
  Structure, 13, 1643-1651.
PDB code: 2b4s
15343278 N.J.Dibb, S.M.Dilworth, and C.D.Mol (2004).
Switching on kinases: oncogenic activation of BRAF and the PDGFR family.
  Nat Rev Cancer, 4, 718-727.  
15173825 S.R.Hubbard (2004).
Juxtamembrane autoinhibition in receptor tyrosine kinases.
  Nat Rev Mol Cell Biol, 5, 464-471.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.