PDBsum entry 2auh

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protein metals Protein-protein interface(s) links
Transferase/signaling protein PDB id
Jmol PyMol
Protein chains
300 a.a. *
37 a.a. *
_CA ×2
* Residue conservation analysis
PDB id:
Name: Transferase/signaling protein
Title: Crystal structure of the grb14 bps region in complex with the insulin receptor tyrosine kinase
Structure: Insulin receptor. Chain: a. Fragment: tyrosine kinase domain. Synonym: ir, cd220 antigen. Engineered: yes. Growth factor receptor-bound protein 14. Chain: b. Fragment: bps region. Synonym: grb14 adaptor protein.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: insr. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: grb14. Expression_system_taxid: 562
Biol. unit: Dimer (from PQS)
3.20Å     R-factor:   0.223     R-free:   0.254
Authors: R.S.Depetris,J.Hu,I.Gimpelevich,L.J.Holt,R.J.Daly, S.R.Hubbard
Key ref:
R.S.Depetris et al. (2005). Structural basis for inhibition of the insulin receptor by the adaptor protein Grb14. Mol Cell, 20, 325-333. PubMed id: 16246733 DOI: 10.1016/j.molcel.2005.09.001
27-Aug-05     Release date:   01-Nov-05    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P06213  (INSR_HUMAN) -  Insulin receptor
1382 a.a.
300 a.a.*
Protein chain
Pfam   ArchSchema ?
Q14449  (GRB14_HUMAN) -  Growth factor receptor-bound protein 14
540 a.a.
37 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: Chain A: 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!
  Biological process     protein phosphorylation   1 term 
  Biochemical function     protein kinase activity     2 terms  


DOI no: 10.1016/j.molcel.2005.09.001 Mol Cell 20:325-333 (2005)
PubMed id: 16246733  
Structural basis for inhibition of the insulin receptor by the adaptor protein Grb14.
R.S.Depetris, J.Hu, I.Gimpelevich, L.J.Holt, R.J.Daly, S.R.Hubbard.
Grb14, a member of the Grb7 adaptor protein family, possesses a pleckstrin homology (PH) domain, a C-terminal Src homology-2 (SH2) domain, and an intervening stretch of approximately 45 residues known as the BPS region, which is unique to this adaptor family. Previous studies have demonstrated that Grb14 is a tissue-specific negative regulator of insulin receptor signaling and that inhibition is mediated by the BPS region. We have determined the crystal structure of the Grb14 BPS region in complex with the tyrosine kinase domain of the insulin receptor. The structure reveals that the N-terminal portion of the BPS region binds as a pseudosubstrate inhibitor in the substrate peptide binding groove of the kinase. Together with the crystal structure of the SH2 domain, we present a model for the interaction of Grb14 with the insulin receptor, which indicates how Grb14 functions as a selective protein inhibitor of insulin signaling.
  Selected figure(s)  
Figure 1.
Figure 1. Crystal Structure of the Grb14(BPS)-IRK Complex
Figure 4.
Figure 4. Model for the Interaction of Grb14 with the Insulin Receptor
  The above figures are reprinted by permission from Cell Press: Mol Cell (2005, 20, 325-333) copyright 2005.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
22581228 A.K.Manning, M.F.Hivert, R.A.Scott, J.L.Grimsby, N.Bouatia-Naji, H.Chen, D.Rybin, C.T.Liu, L.F.Bielak, I.Prokopenko, N.Amin, D.Barnes, G.Cadby, J.J.Hottenga, E.Ingelsson, A.U.Jackson, T.Johnson, S.Kanoni, C.Ladenvall, V.Lagou, J.Lahti, C.Lecoeur, Y.Liu, M.T.Martinez-Larrad, M.E.Montasser, P.Navarro, J.R.Perry, L.J.Rasmussen-Torvik, P.Salo, N.Sattar, D.Shungin, R.J.Strawbridge, T.Tanaka, C.M.van Duijn, P.An, Andrade, J.S.Andrews, T.Aspelund, M.Atalay, Y.Aulchenko, B.Balkau, S.Bandinelli, J.S.Beckmann, J.P.Beilby, C.Bellis, R.N.Bergman, J.Blangero, M.Boban, M.Boehnke, E.Boerwinkle, L.L.Bonnycastle, D.I.Boomsma, I.B.Borecki, Y.Böttcher, C.Bouchard, E.Brunner, D.Budimir, H.Campbell, O.Carlson, P.S.Chines, R.Clarke, F.S.Collins, A.Corbatón-Anchuelo, D.Couper, Faire, G.V.Dedoussis, P.Deloukas, M.Dimitriou, J.M.Egan, G.Eiriksdottir, M.R.Erdos, J.G.Eriksson, E.Eury, L.Ferrucci, I.Ford, N.G.Forouhi, C.S.Fox, M.G.Franzosi, P.W.Franks, T.M.Frayling, P.Froguel, P.Galan, Geus, B.Gigante, N.L.Glazer, A.Goel, L.Groop, V.Gudnason, G.Hallmans, A.Hamsten, O.Hansson, T.B.Harris, C.Hayward, S.Heath, S.Hercberg, A.A.Hicks, A.Hingorani, A.Hofman, J.Hui, and J.Hung (2012).
A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance.
  Nat Genet, 44, 659-669.  
20973951 C.Sturk, and D.J.Dumont (2010).
Tyrosine phosphorylation of Grb14 by Tie2.
  Cell Commun Signal, 8, 30.  
20890309 V.K.Gupta, A.Rajala, R.J.Daly, and R.V.Rajala (2010).
Growth factor receptor-bound protein 14: a new modulator of photoreceptor-specific cyclic-nucleotide-gated channel.
  EMBO Rep, 11, 861-867.  
19438210 A.Rajala, R.J.Daly, M.Tanito, D.T.Allen, L.J.Holt, E.S.Lobanova, V.Y.Arshavsky, and R.V.Rajala (2009).
Growth factor receptor-bound protein 14 undergoes light-dependent intracellular translocation in rod photoreceptors: functional role in retinal insulin receptor activation.
  Biochemistry, 48, 5563-5572.  
19654617 D.F.Ceccarelli, and F.Sicheri (2009).
Grb-ing hold of insulin signaling.
  Nat Struct Mol Biol, 16, 803-804.  
19936222 D.I.Chasman, G.Paré, S.Mora, J.C.Hopewell, G.Peloso, R.Clarke, L.A.Cupples, A.Hamsten, S.Kathiresan, A.Mälarstig, J.M.Ordovas, S.Ripatti, A.N.Parker, J.P.Miletich, and P.M.Ridker (2009).
Forty-three loci associated with plasma lipoprotein size, concentration, and cholesterol content in genome-wide analysis.
  PLoS Genet, 5, e1000730.  
19879842 K.C.Cheng, R.Klancer, A.Singson, and G.Seydoux (2009).
Regulation of MBK-2/DYRK by CDK-1 and the pseudophosphatases EGG-4 and EGG-5 during the oocyte-to-embryo transition.
  Cell, 139, 560-572.  
19879835 N.K.Tonks (2009).
Pseudophosphatases: grab and hold on.
  Cell, 139, 464-465.  
18761339 R.Bose, and X.Zhang (2009).
The ErbB kinase domain: structural perspectives into kinase activation and inhibition.
  Exp Cell Res, 315, 649-658.  
19648926 R.S.Depetris, J.Wu, and S.R.Hubbard (2009).
Structural and functional studies of the Ras-associating and pleckstrin-homology domains of Grb10 and Grb14.
  Nat Struct Mol Biol, 16, 833-839.
PDB code: 3hk0
18853468 S.Siamakpour-Reihani, H.J.Argiros, L.J.Wilmeth, L.L.Haas, T.A.Peterson, D.L.Johnson, C.B.Shuster, and B.A.Lyons (2009).
The cell migration protein Grb7 associates with transcriptional regulator FHL2 in a Grb7 phosphorylation-dependent manner.
  J Mol Recognit, 22, 9.  
19269802 T.Hunter (2009).
Tyrosine phosphorylation: thirty years and counting.
  Curr Opin Cell Biol, 21, 140-146.  
17894853 C.J.Porter, J.M.Matthews, J.P.Mackay, S.E.Pursglove, J.W.Schmidberger, P.J.Leedman, S.C.Pero, D.N.Krag, M.C.Wilce, and J.A.Wilce (2007).
Grb7 SH2 domain structure and interactions with a cyclic peptide inhibitor of cancer cell migration and proliferation.
  BMC Struct Biol, 7, 58.
PDB code: 2qms
18059449 D.J.Leahy (2007).
A monkey wrench in the kinase machine.
  Nat Struct Mol Biol, 14, 1120-1121.  
17562854 F.M.Smith, L.J.Holt, A.S.Garfield, M.Charalambous, F.Koumanov, M.Perry, R.Bazzani, S.A.Sheardown, B.D.Hegarty, R.J.Lyons, G.J.Cooney, R.J.Daly, and A.Ward (2007).
Mice with a disruption of the imprinted Grb10 gene exhibit altered body composition, glucose homeostasis, and insulin signaling during postnatal life.
  Mol Cell Biol, 27, 5871-5886.  
17535812 S.Kebache, J.Ash, M.G.Annis, J.Hagan, M.Huber, J.Hassard, C.L.Stewart, M.Whiteway, and A.Nantel (2007).
Grb10 and active Raf-1 kinase promote Bad-dependent cell survival.
  J Biol Chem, 282, 21873-21883.  
17306972 S.R.Hubbard, and W.T.Miller (2007).
Receptor tyrosine kinases: mechanisms of activation and signaling.
  Curr Opin Cell Biol, 19, 117-123.  
18046415 X.Zhang, K.A.Pickin, R.Bose, N.Jura, P.A.Cole, and J.Kuriyan (2007).
Inhibition of the EGF receptor by binding of MIG6 to an activating kinase domain interface.
  Nature, 450, 741-744.
PDB codes: 2rf9 2rfd 2rfe
16793553 B.A.Liu, K.Jablonowski, M.Raina, M.Arcé, T.Pawson, and P.D.Nash (2006).
The human and mouse complement of SH2 domain proteins-establishing the boundaries of phosphotyrosine signaling.
  Mol Cell, 22, 851-868.  
16905102 E.Bergamin, J.Wu, and S.R.Hubbard (2006).
Structural basis for phosphotyrosine recognition by suppressor of cytokine signaling-3.
  Structure, 14, 1285-1292.
PDB code: 2hmh
16582879 S.Nouaille, C.Blanquart, V.Zilberfarb, N.Boute, D.Perdereau, J.Roix, A.F.Burnol, and T.Issad (2006).
Interaction with Grb14 results in site-specific regulation of tyrosine phosphorylation of the insulin receptor.
  EMBO Rep, 7, 512-518.  
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 code is shown on the right.