PDBsum entry 2hr7

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protein ligands Protein-protein interface(s) links
Transferase PDB id
Protein chain
466 a.a. *
NAG ×4
SO4 ×8
GOL ×19
Waters ×372
* Residue conservation analysis
PDB id:
Name: Transferase
Title: Insulin receptor (domains 1-3)
Structure: Insulin receptor. Chain: a, b. Fragment: domains 1-3 (residues 28-512). Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: insr. Expressed in: cricetulus griseus. Expression_system_taxid: 10029.
2.32Å     R-factor:   0.197     R-free:   0.231
Authors: T.P.J.Garrett,C.W.Ward
Key ref:
M.Lou et al. (2006). The first three domains of the insulin receptor differ structurally from the insulin-like growth factor 1 receptor in the regions governing ligand specificity. Proc Natl Acad Sci U S A, 103, 12429-12434. PubMed id: 16894147 DOI: 10.1073/pnas.0605395103
19-Jul-06     Release date:   15-Aug-06    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P06213  (INSR_HUMAN) -  Insulin receptor
1382 a.a.
466 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 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
Bound ligand (Het Group name = NAG)
matches with 47.62% similarity
+ [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     ATP binding     2 terms  


DOI no: 10.1073/pnas.0605395103 Proc Natl Acad Sci U S A 103:12429-12434 (2006)
PubMed id: 16894147  
The first three domains of the insulin receptor differ structurally from the insulin-like growth factor 1 receptor in the regions governing ligand specificity.
M.Lou, T.P.Garrett, N.M.McKern, P.A.Hoyne, V.C.Epa, J.D.Bentley, G.O.Lovrecz, L.J.Cosgrove, M.J.Frenkel, C.W.Ward.
The insulin receptor (IR) and the type-1 insulin-like growth factor receptor (IGF1R) are homologous multidomain proteins that bind insulin and IGF with differing specificity. Here we report the crystal structure of the first three domains (L1-CR-L2) of human IR at 2.3 A resolution and compare it with the previously determined structure of the corresponding fragment of IGF1R. The most important differences seen between the two receptors are in the two regions governing ligand specificity. The first is at the corner of the ligand-binding surface of the L1 domain, where the side chain of F39 in IR forms part of the ligand binding surface involving the second (central) beta-sheet. This is very different to the location of its counterpart in IGF1R, S35, which is not involved in ligand binding. The second major difference is in the sixth module of the CR domain, where IR contains a larger loop that protrudes further into the ligand-binding pocket. This module, which governs IGF1-binding specificity, shows negligible sequence identity, significantly more alpha-helix, an additional disulfide bond, and opposite electrostatic potential compared to that of the IGF1R.
  Selected figure(s)  
Figure 1.
Fig. 1. Comparison of the structures of the L1–CR–L2 domain fragments of IR (molecules 1 and 2) and IGF1R. Helices are indicated by curled red ribbons, and -strands are indicated by broad arrows. The blue, green, and yellow -strands depict the three prominent parallel -sheets within the L1 and L2 domains. The -strands in the cys-rich domains are colored orange. The side chains of disulfide-linked cysteine residues are depicted as yellow sticks. IGF1R structure is from ref. 4. Two notable regions of difference between IR and IGF1R are near IR F39 (box) and the larger loop in module 6 of the cys-rich domain (circle).
Figure 4.
Fig. 4. Electrostatic potentials calculated for the L1 and CR domains of IR and IGF1R. Surface representation colored by electrostatic potential ranging in magnitude from –10 kT/e (dark red) to 10 kT/e (dark blue), where k is the Boltzmann constant, T is the temperature, and e the magnitude of the electron charge. The electrostatic potentials were calculated by using GRASP version 1.3.6 (28), placing partial charges on side chain terminal atoms of Asp, Glu, Arg, and Lys amino acids and all backbone atoms. (A) The ligand binding face of the L1 domain of IR viewed as in Fig. 5. (B) The L1–CR–L2 fragment of IR viewed from the side with the CR region at the back. The electrostatic potential of the CR region lining the putative ligand-binding pocket of IR is predominantly positive. (C) The ligand binding face of the L1 domain of IGF1R viewed as A. (D) The L1–CR–L2 fragment of IGF1R viewed from the side with the CR region at the back. The electrostatic potential of the CR region lining the putative ligand-binding pocket of IGF1R is predominantly negative.
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
23302862 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, and M.C.Lawrence (2013).
How insulin engages its primary binding site on the insulin receptor.
  Nature, 493, 241-245.
PDB codes: 3w11 3w12 3w13 3w14
21318406 E.Raffan, M.A.Soos, N.Rocha, A.Tuthill, A.R.Thomsen, C.S.Hyden, J.W.Gregory, P.Hindmarsh, M.Dattani, E.Cochran, J.Al Kaabi, P.Gorden, I.Barroso, N.Morling, S.O'Rahilly, and R.K.Semple (2011).
Founder effect in the Horn of Africa for an insulin receptor mutation that may impair receptor recycling.
  Diabetologia, 54, 1057-1065.  
20348418 B.J.Smith, K.Huang, G.Kong, S.J.Chan, S.Nakagawa, J.G.Menting, S.Q.Hu, J.Whittaker, D.F.Steiner, P.G.Katsoyannis, C.W.Ward, M.A.Weiss, and M.C.Lawrence (2010).
Structural resolution of a tandem hormone-binding element in the insulin receptor and its implications for design of peptide agonists.
  Proc Natl Acad Sci U S A, 107, 6771-6776.
PDB code: 3loh
20352052 H.You, W.Zhang, M.K.Jones, G.N.Gobert, J.Mulvenna, G.Rees, M.Spanevello, D.Blair, M.Duke, K.Brehm, and D.P.McManus (2010).
Cloning and characterisation of Schistosoma japonicum insulin receptors.
  PLoS One, 5, e9868.  
19101970 A.K.Petrus, D.G.Allis, R.P.Smith, T.J.Fairchild, and R.P.Doyle (2009).
Exploring the implications of vitamin B12 conjugation to insulin on insulin receptor binding.
  ChemMedChem, 4, 421-426.  
19416159 A.M.Svendsen, M.Vrecl, L.Knudsen, A.Heding, J.D.Wade, R.A.Bathgate, P.De Meyts, and J.Nøhr (2009).
Dimerization and negative cooperativity in the relaxin family peptide receptors.
  Ann N Y Acad Sci, 1160, 54-59.  
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.  
19578119 J.Saegusa, S.Yamaji, K.Ieguchi, C.Y.Wu, K.S.Lam, F.T.Liu, Y.K.Takada, and Y.Takada (2009).
The direct binding of insulin-like growth factor-1 (IGF-1) to integrin alphavbeta3 is involved in IGF-1 signaling.
  J Biol Chem, 284, 24106-24114.  
19773552 M.Zhao, Z.L.Wan, L.Whittaker, B.Xu, N.B.Phillips, P.G.Katsoyannis, F.Ismail-Beigi, J.Whittaker, and M.A.Weiss (2009).
Design of an insulin analog with enhanced receptor binding selectivity: rationale, structure, and therapeutic implications.
  J Biol Chem, 284, 32178-32187.
PDB code: 3fq9
19225456 V.V.Kiselyov, S.Versteyhe, L.Gauguin, and P.De Meyts (2009).
Harmonic oscillator model of the insulin and IGF1 receptors' allosteric binding and activation.
  Mol Syst Biol, 5, 243.  
18350600 K.Breuhahn, and P.Schirmacher (2008).
Reactivation of the insulin-like growth factor-II signaling pathway in human hepatocellular carcinoma.
  World J Gastroenterol, 14, 1690-1698.  
17957771 L.G.Sparrow, M.C.Lawrence, J.J.Gorman, P.M.Strike, C.P.Robinson, N.M.McKern, and C.W.Ward (2008).
N-linked glycans of the human insulin receptor and their distribution over the crystal structure.
  Proteins, 71, 426-439.  
18989367 M.E.Rentería, N.S.Gandhi, P.Vinuesa, E.Helmerhorst, and R.L.Mancera (2008).
A comparative structural bioinformatics analysis of the insulin receptor family ectodomain based on phylogenetic information.
  PLoS ONE, 3, e3667.  
18640841 P.De Meyts (2008).
The insulin receptor: a prototype for dimeric, allosteric membrane receptors?
  Trends Biochem Sci, 33, 376-384.  
18316333 R.Masnikosa, A.Nikolić, and O.Nedić (2008).
Affinity modulation of human placental insulin and insulin-like growth factor receptors by lectins.
  J Biochem, 143, 813-820.  
17318838 A.Garza-Garcia, D.S.Patel, D.Gems, and P.C.Driscoll (2007).
RILM: a web-based resource to aid comparative and functional analysis of the insulin and IGF-1 receptor family.
  Hum Mutat, 28, 660-668.  
17280834 C.W.Ward, M.C.Lawrence, V.A.Streltsov, T.E.Adams, and N.M.McKern (2007).
The insulin and EGF receptor structures: new insights into ligand-induced receptor activation.
  Trends Biochem Sci, 32, 129-137.  
17697999 J.P.Dawson, Z.Bu, and M.A.Lemmon (2007).
Ligand-induced structural transitions in ErbB receptor extracellular domains.
  Structure, 15, 942-954.  
17078079 L.G.Sparrow, J.J.Gorman, P.M.Strike, C.P.Robinson, N.M.McKern, V.C.Epa, and C.W.Ward (2007).
The location and characterisation of the O-linked glycans of the human insulin receptor.
  Proteins, 66, 261-265.  
17851071 M.C.Lawrence, N.M.McKern, and C.W.Ward (2007).
Insulin receptor structure and its implications for the IGF-1 receptor.
  Curr Opin Struct Biol, 17, 699-705.  
17181541 N.Khayath, J.Vicogne, A.Ahier, A.BenYounes, C.Konrad, J.Trolet, E.Viscogliosi, K.Brehm, and C.Dissous (2007).
Diversification of the insulin receptor family in the helminth parasite Schistosoma mansoni.
  FEBS J, 274, 659-676.  
17898809 Y.Tao, V.Pinzi, J.Bourhis, and E.Deutsch (2007).
Mechanisms of disease: signaling of the insulin-like growth factor 1 receptor pathway--therapeutic perspectives in cancer.
  Nat Clin Pract Oncol, 4, 591-602.  
16957736 N.M.McKern, M.C.Lawrence, V.A.Streltsov, M.Z.Lou, T.E.Adams, G.O.Lovrecz, T.C.Elleman, K.M.Richards, J.D.Bentley, P.A.Pilling, P.A.Hoyne, K.A.Cartledge, T.M.Pham, J.L.Lewis, S.E.Sankovich, V.Stoichevska, E.Da Silva, C.P.Robinson, M.J.Frenkel, L.G.Sparrow, R.T.Fernley, V.C.Epa, and C.W.Ward (2006).
Structure of the insulin receptor ectodomain reveals a folded-over conformation.
  Nature, 443, 218-221.
PDB code: 2dtg
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.