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PDBsum entry 1igr
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Hormone receptor PDB id
1igr

 

 

 

 

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Contents
Protein chain
471 a.a. *
Ligands
NAG-NAG-FUC
NAG-NAG-BMA-MAN-
FUC
NAG ×2
SO4 ×8
Waters ×48
* Residue conservation analysis
PDB id:
1igr
Name: Hormone receptor
Title: Type 1 insulin-like growth factor receptor (domains 1-3)
Structure: Insulin-like growth factor receptor 1. Chain: a. Fragment: unp residues 31-492. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Organ: placenta. Cellular_location: cytoplasmic membrane. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Expression_system_cell_line: lec8. Expression_system_collection: crl:1737.
Resolution:
2.60Å     R-factor:   0.237     R-free:   0.304
Authors: T.P.J.Garrett,N.M.Mckern,M.Lou,M.J.Frenkel,J.D.Bentley,G.O.Lovrecz, T.C.Elleman,L.J.Cosgrove,C.W.Ward
Key ref:
T.P.Garrett et al. (1998). Crystal structure of the first three domains of the type-1 insulin-like growth factor receptor. Nature, 394, 395-399. PubMed id: 9690478 DOI: 10.1038/28668
Date:
28-Sep-98     Release date:   27-Sep-99    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
P08069  (IGF1R_HUMAN) -  Insulin-like growth factor 1 receptor from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		1367 a.a.
471 a.a.*
Key:    Secondary structure  CATH domain
* PDB and UniProt seqs differ at 12 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.2.7.10.1  - receptor protein-tyrosine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H+
L-tyrosyl-[protein]
 + ATP
 = O-phospho-L-tyrosyl-[protein]
Bound ligand (Het Group name = NAG)
matches with 41.38% similarity 		+ ADP
 + H(+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    Added reference    
 
 
DOI no: 10.1038/28668 Nature 394:395-399 (1998)
PubMed id: 9690478  
 
 
Crystal structure of the first three domains of the type-1 insulin-like growth factor receptor.
T.P.Garrett, N.M.McKern, M.Lou, M.J.Frenkel, J.D.Bentley, G.O.Lovrecz, T.C.Elleman, L.J.Cosgrove, C.W.Ward.
 
  ABSTRACT  
 
The type-1 insulin-like growth-factor receptor (IGF-1R) and insulin receptor (IR) are closely related members of the tyrosine-kinase receptor superfamily. IR is essential for glucose homeostasis, whereas IGF-1R is involved in both normal growth and development and malignant transformation. Homologues of these receptors are found in animals as simple as cnidarians. The epidermal growth-factor receptor (EGFR) family is closely related to the IR family and has significant sequence identity to the extracellular portion we describe here. We now present the structure of the first three domains of IGF-IR (L1-Cys-rich-L2) determined to 2.6 A resolution. The L domains each consist of a single-stranded right-handed beta-helix. The Cys-rich region is composed of eight disulphide-bonded modules, seven of which form a rod-shaped domain with modules associated in an unusual manner. The three domains surround a central space of sufficient size to accommodate a ligand molecule. Although the fragment (residues 1-462) does not bind ligand, many of the determinants responsible for hormone binding and ligand specificity map to this central site. This structure therefore shows how the IR subfamily might interact with their ligands.
 
  Selected figure(s)  
 
Figure 1.
Figure 1 Polypeptide fold for residues 1-459 of IGF-1R. The L1 domain is at the top, viewed from the N-terminal end. The space at the centre is of sufficient size to accommodate IGF-I. Helices are indicated by curled ribbon and -strands by broad arrows. Residues referred to in the text are labelled and marked as white spheres, and disulphide bonds are shown as yellow sticks. The white arrow near the centre of the figure indicates the view direction for Fig. 5. 		Figure 3.
Figure 3 Stereo view of a superposition of the L1 (white) and L2 (black) domains. Residue numbers above are for L1 and below for L2. The side chain of Trp 176, which protrudes into the core of L1, is shown by a ball-and-stick representation.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (1998, 394, 395-399) copyright 1998.  
  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 5kqv
21204214 M.L.Cunningham, J.A.Horst, M.J.Rieder, A.V.Hing, I.B.Stanaway, S.S.Park, R.Samudrala, and M.L.Speltz (2011).
IGF1R variants associated with isolated single suture craniosynostosis.
  Am J Med Genet A, 155, 91-97.  
20339196 I.Takahashi, Y.Yamada, H.Kadowaki, M.Horikoshi, T.Kadowaki, T.Narita, S.Tsuchida, A.Noguchi, A.Koizumi, and T.Takahashi (2010).
Phenotypical variety of insulin resistance in a family with a novel mutation of the insulin receptor gene.
  Endocr J, 57, 509-516.  
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.  
19390622 J.F.Flynn, C.Wong, and J.M.Wu (2009).
Anti-EGFR Therapy: Mechanism and Advances in Clinical Efficacy in Breast Cancer.
  J Oncol, 2009, 526963.  
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.  
19367255 N.Wang, L.Fallavollita, L.Nguyen, J.Burnier, M.Rafei, J.Galipeau, S.Yakar, and P.Brodt (2009).
Autologous bone marrow stromal cells genetically engineered to secrete an igf-I receptor decoy prevent the growth of liver metastases.
  Mol Ther, 17, 1241-1249.  
19995694 P.Vasas, M.C.Winslet, and Y.Y.Shi (2009).
[The role of insulin-like growth factors (IGF) in cell division processes and in malignancy]
  Orv Hetil, 150, 2308-2312.  
19610618 R.Li, A.Pourpak, and S.W.Morris (2009).
Inhibition of the insulin-like growth factor-1 receptor (IGF1R) tyrosine kinase as a novel cancer therapy approach.
  J Med Chem, 52, 4981-5004.  
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.  
18316725 Y.Suh, G.Atzmon, M.O.Cho, D.Hwang, B.Liu, D.J.Leahy, N.Barzilai, and P.Cohen (2008).
Functionally significant insulin-like growth factor I receptor mutations in centenarians.
  Proc Natl Acad Sci U S A, 105, 3438-3442.  
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.  
17608727 F.Morgillo, M.A.Bareschino, R.Bianco, G.Tortora, and F.Ciardiello (2007).
Primary and acquired resistance to anti-EGFR targeted drugs in cancer therapy.
  Differentiation, 75, 788-799.  
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.  
17274834 R.Landgraf (2007).
HER2 therapy. HER2 (ERBB2): functional diversity from structurally conserved building blocks.
  Breast Cancer Res, 9, 202.  
16894147 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, and C.W.Ward (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.
PDB code: 2hr7
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
15936977 A.Denley, L.J.Cosgrove, G.W.Booker, J.C.Wallace, and B.E.Forbes (2005).
Molecular interactions of the IGF system.
  Cytokine Growth Factor Rev, 16, 421-439.  
15701628 E.Schönherr, C.Sunderkötter, R.V.Iozzo, and L.Schaefer (2005).
Decorin, a novel player in the insulin-like growth factor system.
  J Biol Chem, 280, 15767-15772.  
15799978 J.Whittaker, and L.Whittaker (2005).
Characterization of the functional insulin binding epitopes of the full-length insulin receptor.
  J Biol Chem, 280, 20932-20936.  
16127220 M.Hashiramoto, H.Osawa, M.Ando, A.Murakami, T.Nishimiya, M.Nakano, W.Nishida, H.Onuma, and H.Makino (2005).
A nonsense mutation in the Arg345 of the insulin receptor gene in a Japanese type A insulin-resistant patient.
  Endocr J, 52, 499-504.  
15603587 D.Dinakarpandian, V.Morrissette, S.Chaudhary, K.Amini, B.Bennett, and J.D.Van Horn (2004).
An informatics search for the low-molecular weight chromium-binding peptide.
  BMC Chem Biol, 4, 2.  
15057284 X.Qian, T.Karpova, A.M.Sheppard, J.McNally, and D.R.Lowy (2004).
E-cadherin-mediated adhesion inhibits ligand-dependent activation of diverse receptor tyrosine kinases.
  EMBO J, 23, 1739-1748.  
14527402 A.W.Burgess, H.S.Cho, C.Eigenbrot, K.M.Ferguson, T.P.Garrett, D.J.Leahy, M.A.Lemmon, M.X.Sliwkowski, C.W.Ward, and S.Yokoyama (2003).
An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors.
  Mol Cell, 12, 541-552.  
12764141 C.C.Yip, and P.Ottensmeyer (2003).
Three-dimensional structural interactions of insulin and its receptor.
  J Biol Chem, 278, 27329-27332.  
12620237 K.M.Ferguson, M.B.Berger, J.M.Mendrola, H.S.Cho, D.J.Leahy, and M.A.Lemmon (2003).
EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization.
  Mol Cell, 11, 507-517.
PDB code: 1nql
12684539 L.Schäffer, R.E.Brissette, J.C.Spetzler, R.C.Pillutla, S.Østergaard, M.Lennick, J.Brandt, P.W.Fletcher, G.M.Danielsen, K.C.Hsiao, A.S.Andersen, O.Dedova, U.Ribel, T.Hoeg-Jensen, P.H.Hansen, A.J.Blume, J.Markussen, and N.I.Goldstein (2003).
Assembly of high-affinity insulin receptor agonists and antagonists from peptide building blocks.
  Proc Natl Acad Sci U S A, 100, 4435-4439.  
14566968 R.H.McCusker, and J.Novakofski (2003).
Zinc partitions insulin-like growth factors (IGFs) from soluble IGF binding protein (IGFBP)-5 to the cell surface receptors of BC3H-1 muscle cells.
  J Cell Physiol, 197, 388-399.  
14501110 S.Munshi, D.L.Hall, M.Kornienko, P.L.Darke, and L.C.Kuo (2003).
Structure of apo, unactivated insulin-like growth factor-1 receptor kinase at 1.5 A resolution.
  Acta Crystallogr D Biol Crystallogr, 59, 1725-1730.
PDB code: 1p4o
12620236 T.P.Garrett, N.M.McKern, M.Lou, T.C.Elleman, T.E.Adams, G.O.Lovrecz, M.Kofler, R.N.Jorissen, E.C.Nice, A.W.Burgess, and C.W.Ward (2003).
The crystal structure of a truncated ErbB2 ectodomain reveals an active conformation, poised to interact with other ErbB receptors.
  Mol Cell, 11, 495-505.
PDB code: 2a91
12569553 Y.L.Yip, J.Novotny, M.Edwards, and R.L.Ward (2003).
Structural analysis of the ErbB-2 receptor using monoclonal antibodies: Implications for receptor signalling.
  Int J Cancer, 104, 303-309.  
12011054 A.Berezov, J.Chen, Q.Liu, H.T.Zhang, M.I.Greene, and R.Murali (2002).
Disabling receptor ensembles with rationally designed interface peptidomimetics.
  J Biol Chem, 277, 28330-28339.  
11901156 C.Kristensen, A.S.Andersen, S.Ostergaard, P.H.Hansen, and J.Brandt (2002).
Functional reconstitution of insulin receptor binding site from non-binding receptor fragments.
  J Biol Chem, 277, 18340-18345.  
12297050 H.Ogiso, R.Ishitani, O.Nureki, S.Fukai, M.Yamanaka, J.H.Kim, K.Saito, A.Sakamoto, M.Inoue, M.Shirouzu, and S.Yokoyama (2002).
Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains.
  Cell, 110, 775-787.
PDB code: 1ivo
12154198 H.S.Cho, and D.J.Leahy (2002).
Structure of the extracellular region of HER3 reveals an interdomain tether.
  Science, 297, 1330-1333.
PDB code: 1m6b
11985614 J.H.Kim, K.Saito, and S.Yokoyama (2002).
Chimeric receptor analyses of the interactions of the ectodomains of ErbB-1 with epidermal growth factor and of those of ErbB-4 with neuregulin.
  Eur J Biochem, 269, 2323-2329.  
12270939 J.Whittaker, H.Sørensen, V.L.Gadsbøll, and J.Hinrichsen (2002).
Comparison of the functional insulin binding epitopes of the A and B isoforms of the insulin receptor.
  J Biol Chem, 277, 47380-47384.  
11875066 K.H.Surinya, L.Molina, M.A.Soos, J.Brandt, C.Kristensen, and K.Siddle (2002).
Role of insulin receptor dimerization domains in ligand binding, cooperativity, and modulation by anti-receptor antibodies.
  J Biol Chem, 277, 16718-16725.  
11882301 M.Dlakić (2002).
A new family of putative insulin receptor-like proteins in C. elegans.
  Curr Biol, 12, R155-R157.  
12105206 M.Santra, C.C.Reed, and R.V.Iozzo (2002).
Decorin binds to a narrow region of the epidermal growth factor (EGF) receptor, partially overlapping but distinct from the EGF-binding epitope.
  J Biol Chem, 277, 35671-35681.  
12360255 P.De Meyts, and J.Whittaker (2002).
Structural biology of insulin and IGF1 receptors: implications for drug design.
  Nat Rev Drug Discov, 1, 769-783.  
12297049 T.P.Garrett, N.M.McKern, M.Lou, T.C.Elleman, T.E.Adams, G.O.Lovrecz, H.J.Zhu, F.Walker, M.J.Frenkel, P.A.Hoyne, R.N.Jorissen, E.C.Nice, A.W.Burgess, and C.W.Ward (2002).
Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor alpha.
  Cell, 110, 763-773.
PDB code: 1mox
11504559 C.W.Ward, and T.P.Garrett (2001).
The relationship between the L1 and L2 domains of the insulin and epidermal growth factor receptors and leucine-rich repeat modules.
  BMC Bioinformatics, 2, 4.  
11376122 C.W.Ward, T.P.Garrett, N.M.McKern, M.Lou, L.J.Cosgrove, L.G.Sparrow, M.J.Frenkel, P.A.Hoyne, T.C.Elleman, T.E.Adams, G.O.Lovrecz, L.J.Lawrence, and P.A.Tulloch (2001).
The three dimensional structure of the type I insulin-like growth factor receptor.
  Mol Pathol, 54, 125-132.  
11555649 E.Singer, R.Landgraf, T.Horan, D.Slamon, and D.Eisenberg (2001).
Identification of a heregulin binding site in HER3 extracellular domain.
  J Biol Chem, 276, 44266-44274.  
11470818 F.Li, J.Chen, M.Izumi, M.C.Butler, S.M.Keezer, and D.M.Gilbert (2001).
The replication timing program of the Chinese hamster beta-globin locus is established coincident with its repositioning near peripheral heterochromatin in early G1 phase.
  J Cell Biol, 154, 283-292.  
11500492 J.Whittaker, A.V.Groth, D.C.Mynarcik, L.Pluzek, V.L.Gadsbøll, and L.J.Whittaker (2001).
Alanine scanning mutagenesis of a type 1 insulin-like growth factor receptor ligand binding site.
  J Biol Chem, 276, 43980-43986.  
11517220 M.A.Weiss, Q.X.Hua, W.Jia, S.H.Nakagawa, Y.C.Chu, S.Q.Hu, and P.G.Katsoyannis (2001).
Activities of monomeric insulin analogs at position A8 are uncorrelated with their thermodynamic stabilities.
  J Biol Chem, 276, 40018-40024.  
11169925 A.J.Blume, J.Beasley, and N.I.Goldstein (2000).
The use of peptides in Diogenesis: a novel approach to drug discovery and phenomics.
  Biopolymers, 55, 347-356.  
11050437 B.Kobe, and A.V.Kajava (2000).
When protein folding is simplified to protein coiling: the continuum of solenoid protein structures.
  Trends Biochem Sci, 25, 509-515.  
11015187 F.P.Ottensmeyer, D.R.Beniac, R.Z.Luo, and C.C.Yip (2000).
Mechanism of transmembrane signaling: insulin binding and the insulin receptor.
  Biochemistry, 39, 12103-12112.  
10753817 M.C.Deller, and E.Yvonne Jones (2000).
Cell surface receptors.
  Curr Opin Struct Biol, 10, 213-219.  
  10716183 R.N.Jorissen, V.C.Epa, H.R.Treutlein, T.P.Garrett, C.W.Ward, and A.W.Burgess (2000).
Characterization of a comparative model of the extracellular domain of the epidermal growth factor receptor.
  Protein Sci, 9, 310-324.
PDB codes: 1dnq 1dnr
10966463 S.R.Hubbard, and J.H.Till (2000).
Protein tyrosine kinase structure and function.
  Annu Rev Biochem, 69, 373-398.  
10378263 B.Kobe, T.Gleichmann, J.Horne, I.G.Jennings, P.D.Scotney, and T.Teh (1999).
Turn up the HEAT.
  Structure, 7, R91-R97.  
10562539 B.R.Crane, R.J.Rosenfeld, A.S.Arvai, D.K.Ghosh, S.Ghosh, J.A.Tainer, D.J.Stuehr, and E.D.Getzoff (1999).
N-terminal domain swapping and metal ion binding in nitric oxide synthase dimerization.
  EMBO J, 18, 6271-6281.
PDB codes: 1df1 1qom
10601304 C.Kristensen, F.C.Wiberg, and A.S.Andersen (1999).
Specificity of insulin and insulin-like growth factor I receptors investigated using chimeric mini-receptors. Role of C-terminal of receptor alpha subunit.
  J Biol Chem, 274, 37351-37356.  
10574975 C.N.Woldin, F.S.Hing, J.Lee, P.F.Pilch, and G.G.Shipley (1999).
Structural studies of the detergent-solubilized and vesicle-reconstituted insulin receptor.
  J Biol Chem, 274, 34981-34992.  
10187777 G.Han, and D.R.Hampson (1999).
Ligand binding to the amino-terminal domain of the mGluR4 subtype of metabotropic glutamate receptor.
  J Biol Chem, 274, 10008-10013.  
  10091652 G.Kurapkat, M.Siedentop, H.G.Gattner, M.Hagelstein, D.Brandenburg, J.Grötzinger, and A.Wollmer (1999).
The solution structure of a superpotent B-chain-shortened single-replacement insulin analogue.
  Protein Sci, 8, 499-508.
PDB code: 1bzv
10497195 M.L.Saxon, and D.C.Lee (1999).
Mutagenesis reveals a role for epidermal growth factor receptor extracellular subdomain IV in ligand binding.
  J Biol Chem, 274, 28356-28362.  
10373457 M.Rouard, J.Bass, F.Grigorescu, T.P.Garrett, C.W.Ward, G.Lipkind, C.Jaffiole, D.F.Steiner, and G.I.Bell (1999).
Congenital insulin resistance associated with a conformational alteration in a conserved beta-sheet in the insulin receptor L1 domain.
  J Biol Chem, 274, 18487-18491.  
10446056 R.Z.Luo, D.R.Beniac, A.Fernandes, C.C.Yip, and F.P.Ottensmeyer (1999).
Quaternary structure of the insulin-insulin receptor complex.
  Science, 285, 1077-1080.  
9868364 T.D.Mulhern, G.W.Booker, and L.Cosgrove (1998).
A third fibronectin-type-III domain in the insulin-family receptors.
  Trends Biochem Sci, 23, 465-466.  
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.

 

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