PDBsum entry 1rqq

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protein ligands metals Protein-protein interface(s) links
Transferase/signaling protein PDB id
Protein chains
297 a.a. *
83 a.a. *
14 a.a. *
13 a.a. *
112 ×2
_MN ×2
Waters ×79
* Residue conservation analysis
PDB id:
Name: Transferase/signaling protein
Title: Crystal structure of the insulin receptor kinase in complex with the sh2 domain of aps
Structure: Insulin receptor. Chain: a, b. Fragment: kinase domain. Synonym: ir. Engineered: yes. Mutation: yes. Adaptor protein aps. Chain: c, d. Fragment: sh2 domain.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: insr. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9. Rattus norvegicus. Norway rat.
Biol. unit: Hexamer (from PQS)
2.60Å     R-factor:   0.229     R-free:   0.277
Authors: J.Hu,J.Liu,R.Ghirlando,A.R.Saltiel,S.R.Hubbard
Key ref:
J.Hu et al. (2003). Structural basis for recruitment of the adaptor protein APS to the activated insulin receptor. Mol Cell, 12, 1379-1389. PubMed id: 14690593 DOI: 10.1016/S1097-2765(03)00487-8
06-Dec-03     Release date:   30-Dec-03    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P06213  (INSR_HUMAN) -  Insulin receptor
1382 a.a.
297 a.a.*
Protein chains
Pfam   ArchSchema ?
Q9Z200  (SH2B2_RAT) -  SH2B adapter protein 2
621 a.a.
83 a.a.
Protein chain
No UniProt id for this chain
Struc: 14 a.a.
Protein chain
No UniProt id for this chain
Struc: 13 a.a.
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: Chains A, B: E.C.  - Receptor protein-tyrosine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate
Bound ligand (Het Group name = 112)
matches with 83.00% similarity
+ [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     5 terms  


DOI no: 10.1016/S1097-2765(03)00487-8 Mol Cell 12:1379-1389 (2003)
PubMed id: 14690593  
Structural basis for recruitment of the adaptor protein APS to the activated insulin receptor.
J.Hu, J.Liu, R.Ghirlando, A.R.Saltiel, S.R.Hubbard.
The adaptor protein APS is a substrate of the insulin receptor and couples receptor activation with phosphorylation of Cbl to facilitate glucose uptake. The interaction with the activated insulin receptor is mediated by the Src homology 2 (SH2) domain of APS. Here, we present the crystal structure of the APS SH2 domain in complex with the phosphorylated tyrosine kinase domain of the insulin receptor. The structure reveals a novel dimeric configuration of the APS SH2 domain, wherein the C-terminal half of each protomer is structurally divergent from conventional, monomeric SH2 domains. The APS SH2 dimer engages two kinase molecules, with pTyr-1158 of the kinase activation loop bound in the canonical phosphotyrosine binding pocket of the SH2 domain and a second phosphotyrosine, pTyr-1162, coordinated by two lysine residues in beta strand D. This structure provides a molecular visualization of one of the initial downstream recruitment events following insulin activation of its dimeric receptor.
  Selected figure(s)  
Figure 2.
Figure 2. Crystal Structure of the APS(SH2)-IRK ComplexRibbon diagram (top) and all-atom representation (bottom) of the APS(SH2)-IRK structure. The noncrystallographic 2-fold axis is vertical. The two IRK molecules are colored cyan, except for the activation loop, which is colored yellow. The two APS(SH2) protomers are colored green and purple. The three phosphotyrosine residues in the IRK activation loop are shown in ball-and-stick representation, with carbon atoms colored yellow, oxygen atoms colored red, and phosphorus atoms colored black. The bisubstrate inhibitor is colored orange, with the peptide portion shown in ribbon/coil representation, and the substrate tyrosine, linker, and ATPγS atoms shown in ball-and-stick representation. The N termini of the IRK molecules, which lead into the juxtamembrane region (34 residues to the transmembrane helix), are indicated, as are the C termini of the APS(SH2) protomers. The C-terminal tyrosine phosphorylation site in APS (Tyr-618) is 132 residues from the end of the SH2 domain.
Figure 3.
Figure 3. Mode of Binding of the IRK Activation Loop to the APS SH2 Domain(A) Stereo view of the interactions between APS(SH2) and the IRK activation loop. The IRK activation loop is colored yellow and the APS SH2 protomer to which it binds is colored green. For clarity, the other APS SH2 protomer is not shown. Hydrogen bonds/salt bridges are shown with black dashed lines.(B) Path of the IRK activation loop across the APS SH2 domain surface. A ribbon diagram of the APS SH2 dimer is shown, with the two protomers colored green and purple. The Cα trace of the IRK activation loop proximal to pTyr-1158 and pTyr-1162 is colored yellow, with the side chains of the two phosphotyrosines shown in ball-and-stick representation. The SH2 domains of Src (Waksman et al., 1993) and Grb2 (Rahuel et al., 1996) with bound peptides were superimposed (core β sheets) with the green APS SH2 protomer, and the phosphopeptides from the superposition, PQpYEEI for Src (cyan) and PSp YVNVQN for Grb2 (orange), are displayed as Cα traces, with the phosphotyrosines shown in ball-and-stick representation. The N- and C termini of the phosphopeptides are indicated by “N” and “C” of the appropriate color. The two disordered residues between βD and αB in the APS SH2 protomers are represented by small spheres.
  The above figures are reprinted by permission from Cell Press: Mol Cell (2003, 12, 1379-1389) copyright 2003.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
22617471 D.Leto, and A.R.Saltiel (2012).
Regulation of glucose transport by insulin: traffic control of GLUT4.
  Nat Rev Mol Cell Biol, 13, 383-396.  
20561261 F.Vlad, M.J.Droillard, B.Valot, M.Khafif, A.Rodrigues, M.Brault, M.Zivy, P.L.Rodriguez, S.Merlot, and C.Laurière (2010).
Phospho-site mapping, genetic and in planta activation studies reveal key aspects of the different phosphorylation mechanisms involved in activation of SnRK2s.
  Plant J, 63, 778-790.  
19654617 D.F.Ceccarelli, and F.Sicheri (2009).
Grb-ing hold of insulin signaling.
  Nat Struct Mol Biol, 16, 803-804.  
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
19293402 S.Gery, Q.Cao, S.Gueller, H.Xing, A.Tefferi, and H.P.Koeffler (2009).
Lnk inhibits myeloproliferative disorder-associated JAK2 mutant, JAK2V617F.
  J Leukoc Biol, 85, 957-965.  
19001411 S.Hanke, and M.Mann (2009).
The phosphotyrosine interactome of the insulin receptor family and its substrates IRS-1 and IRS-2.
  Mol Cell Proteomics, 8, 519-534.  
19269802 T.Hunter (2009).
Tyrosine phosphorylation: thirty years and counting.
  Curr Opin Cell Biol, 21, 140-146.  
19016312 A.Belfiore, and F.Frasca (2008).
IGF and insulin receptor signaling in breast cancer.
  J Mammary Gland Biol Neoplasia, 13, 381-406.  
18239682 A.C.Pike, P.Rellos, F.H.Niesen, A.Turnbull, A.W.Oliver, S.A.Parker, B.E.Turk, L.H.Pearl, and S.Knapp (2008).
Activation segment dimerization: a mechanism for kinase autophosphorylation of non-consensus sites.
  EMBO J, 27, 704-714.
PDB codes: 2j51 2j7t 2j90 2jfl 2jfm 2uv2
18465356 F.Frasca, G.Pandini, L.Sciacca, V.Pezzino, S.Squatrito, A.Belfiore, and R.Vigneri (2008).
The role of insulin receptors and IGF-I receptors in cancer and other diseases.
  Arch Physiol Biochem, 114, 23-37.  
18566589 J.Wu, W.Li, B.P.Craddock, K.W.Foreman, M.J.Mulvihill, Q.S.Ji, W.T.Miller, and S.R.Hubbard (2008).
Small-molecule inhibition and activation-loop trans-phosphorylation of the IGF1 receptor.
  EMBO J, 27, 1985-1994.
PDB code: 3d94
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
18923524 Y.Chen, J.Takita, Y.L.Choi, M.Kato, M.Ohira, M.Sanada, L.Wang, M.Soda, A.Kikuchi, T.Igarashi, A.Nakagawara, Y.Hayashi, H.Mano, and S.Ogawa (2008).
Oncogenic mutations of ALK kinase in neuroblastoma.
  Nature, 455, 971-974.  
17635922 G.Kozlov, P.Peschard, B.Zimmerman, T.Lin, T.Moldoveanu, N.Mansur-Azzam, K.Gehring, and M.Park (2007).
Structural basis for UBA-mediated dimerization of c-Cbl ubiquitin ligase.
  J Biol Chem, 282, 27547-27555.
PDB code: 2oo9
17102568 K.Kishi, K.Mawatari, K.Sakai-Wakamatsu, T.Yuasa, M.Wang, M.Ogura-Sawa, Y.Nakaya, S.Hatakeyama, and Y.Ebina (2007).
APS-mediated ubiquitination of the insulin receptor enhances its internalization, but does not induce its degradation.
  Endocr J, 54, 77-88.  
17471236 S.Donatello, A.Fiorino, D.Degl'Innocenti, L.Alberti, C.Miranda, L.Gorla, I.Bongarzone, M.G.Rizzetti, M.A.Pierotti, and M.G.Borrello (2007).
SH2B1beta adaptor is a key enhancer of RET tyrosine kinase signaling.
  Oncogene, 26, 6546-6559.  
17403369 S.Huang, and M.P.Czech (2007).
The GLUT4 glucose transporter.
  Cell Metab, 5, 237-252.  
17306972 S.R.Hubbard, and W.T.Miller (2007).
Receptor tyrosine kinases: mechanisms of activation and signaling.
  Curr Opin Cell Biol, 19, 117-123.  
17322911 T.Pawson, and N.Warner (2007).
Oncogenic re-wiring of cellular signaling pathways.
  Oncogene, 26, 1268-1275.  
16980311 A.M.Burza, I.Pekala, J.Sikora, P.Siedlecki, P.Małagocki, M.Bucholc, L.Koper, P.Zielenkiewicz, M.Dadlez, and G.Dobrowolska (2006).
Nicotiana tabacum osmotic stress-activated kinase is regulated by phosphorylation on Ser-154 and Ser-158 in the kinase activation loop.
  J Biol Chem, 281, 34299-34311.  
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.  
16829979 B.T.Seet, I.Dikic, M.M.Zhou, and T.Pawson (2006).
Reading protein modifications with interaction domains.
  Nat Rev Mol Cell Biol, 7, 473-483.  
16741904 G.Swaminathan, and A.Y.Tsygankov (2006).
The Cbl family proteins: ring leaders in regulation of cell signaling.
  J Cell Physiol, 209, 21-43.  
16914724 J.H.Kurzer, P.Saharinen, O.Silvennoinen, and C.Carter-Su (2006).
Binding of SH2-B family members within a potential negative regulatory region maintains JAK2 in an active state.
  Mol Cell Biol, 26, 6381-6394.  
15841400 C.J.Porter, M.C.Wilce, J.P.Mackay, P.Leedman, and J.A.Wilce (2005).
Grb7-SH2 domain dimerisation is affected by a single point mutation.
  Eur Biophys J, 34, 454-460.  
15737992 J.Hu, and S.R.Hubbard (2005).
Structural characterization of a novel Cbl phosphotyrosine recognition motif in the APS family of adapter proteins.
  J Biol Chem, 280, 18943-18949.
PDB code: 1yvh
16141217 K.D.Katsanakis, and T.S.Pillay (2005).
Cross-talk between the two divergent insulin signaling pathways is revealed by the protein kinase B (Akt)-mediated phosphorylation of adapter protein APS on serine 588.
  J Biol Chem, 280, 37827-37832.  
16243711 L.J.Holt, and R.J.Daly (2005).
Adapter protein connections: the MRL and Grb7 protein families.
  Growth Factors, 23, 193-201.  
15767667 M.Nishi, E.D.Werner, B.C.Oh, J.D.Frantz, S.Dhe-Paganon, L.Hansen, J.Lee, and S.E.Shoelson (2005).
Kinase activation through dimerization by human SH2-B.
  Mol Cell Biol, 25, 2607-2621.  
15590623 P.Bhanot, K.Schauer, I.Coppens, and V.Nussenzweig (2005).
A surface phospholipase is involved in the migration of plasmodium sporozoites through cells.
  J Biol Chem, 280, 6752-6760.  
16246733 R.S.Depetris, J.Hu, I.Gimpelevich, L.J.Holt, R.J.Daly, and S.R.Hubbard (2005).
Structural basis for inhibition of the insulin receptor by the adaptor protein Grb14.
  Mol Cell, 20, 325-333.
PDB codes: 2aug 2auh
15507211 B.Canagarajah, F.C.Leskow, J.Y.Ho, H.Mischak, L.F.Saidi, M.G.Kazanietz, and J.H.Hurley (2004).
Structural mechanism for lipid activation of the Rac-specific GAP, beta2-chimaerin.
  Cell, 119, 407-418.
PDB code: 1xa6
15314154 C.Duan, H.Yang, M.F.White, and L.Rui (2004).
Disruption of the SH2-B gene causes age-dependent insulin resistance and glucose intolerance.
  Mol Cell Biol, 24, 7435-7443.  
15383275 C.Marshall, and W.Müller-Esterl (2004).
Spotlight on cellular signaling.
  Mol Cell, 15, 849-852.  
14982928 K.Duda, Y.I.Chi, and S.E.Shoelson (2004).
Structural basis for HNF-4alpha activation by ligand and coactivator binding.
  J Biol Chem, 279, 23311-23316.
PDB code: 1pzl
  16307172 L.Chang, S.H.Chiang, and A.R.Saltiel (2004).
Insulin signaling and the regulation of glucose transport.
  Mol Med, 10, 65-71.  
15280876 M.A.Lemmon, and S.J.Smerdon (2004).
Signaling by the sea.
  Nat Struct Mol Biol, 11, 682-685.  
15378031 S.Dhe-Paganon, E.D.Werner, M.Nishi, L.Hansen, Y.I.Chi, and S.E.Shoelson (2004).
A phenylalanine zipper mediates APS dimerization.
  Nat Struct Mol Biol, 11, 968-974.
PDB code: 1q2h
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.