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PDBsum entry 1djs
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protein ligands Protein-protein interface(s) links
Hormone/growth factor/receptor PDB id
1djs

 

 

 

 

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Contents
Protein chains
206 a.a. *
135 a.a. *
Ligands
SO4 ×9
Waters ×319
* Residue conservation analysis
PDB id:
1djs
Name: Hormone/growth factor/receptor
Title: Ligand-binding portion of fibroblast growth factor receptor 2 in complex with fgf1
Structure: Protein (fibroblast growth factor receptor 2). Chain: a. Fragment: ig-like domains 2 and 3. Engineered: yes. Mutation: yes. Protein (fibroblast growth factor 1). Chain: b. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562
Biol. unit: Octamer (from PDB file)
Resolution:
2.40Å     R-factor:   0.227     R-free:   0.315
Authors: D.J.Stauber,A.D.Digabriele,W.A.Hendrickson
Key ref:
D.J.Stauber et al. (2000). Structural interactions of fibroblast growth factor receptor with its ligands. Proc Natl Acad Sci U S A, 97, 49-54. PubMed id: 10618369 DOI: 10.1073/pnas.97.1.49
Date:
03-Dec-99     Release date:   12-Jan-00    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
P21802  (FGFR2_HUMAN) -  Fibroblast growth factor receptor 2 from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		821 a.a.
206 a.a.*
Protein chain
P05230  (FGF1_HUMAN) -  Fibroblast growth factor 1 from Homo sapiens
Seq:
Struc: 		155 a.a.
135 a.a.
Key:    Secondary structure  CATH domain
* PDB and UniProt seqs differ at 6 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: Chain A: 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]
 + ADP
 + H(+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    Added reference    
 
 
DOI no: 10.1073/pnas.97.1.49 Proc Natl Acad Sci U S A 97:49-54 (2000)
PubMed id: 10618369  
 
 
Structural interactions of fibroblast growth factor receptor with its ligands.
D.J.Stauber, A.D.DiGabriele, W.A.Hendrickson.
 
  ABSTRACT  
 
Fibroblast growth factors (FGFs) effect cellular responses by binding to FGF receptors (FGFRs). FGF bound to extracellular domains on the FGFR in the presence of heparin activates the cytoplasmic receptor tyrosine kinase through autophosphorylation. We have crystallized a complex between human FGF1 and a two-domain extracellular fragment of human FGFR2. The crystal structure, determined by multiwavelength anomalous diffraction analysis of the selenomethionyl protein, is a dimeric assemblage of 1:1 ligand:receptor complexes. FGF is bound at the junction between the two domains of one FGFR, and two such units are associated through receptor:receptor and secondary ligand:receptor interfaces. Sulfate ion positions appear to mark the course of heparin binding between FGF molecules through a basic region on receptor D2 domains. This dimeric assemblage provides a structural mechanism for FGF signal transduction.
 
  Selected figure(s)  
 
Figure 3.
Fig. 3. Dimeric assemblage. (A) Stereoview of a worm diagram oriented with the diad axis vertical and viewed with the two FGF1:FGFR2 complexes at either side. FGF1 chains are in red, the ipsilateral receptor chain (as rotated 40° from Fig. 1) is in blue, and the contralateral chain is in green. Receptor segments in ligand contacts are in yellow. (B) Close-up of a primary D2 contact viewed at 70° from A. (C) Close-up of a D3 contact viewed at 40° from A. Drawings were made by GRASP (37). 		Figure 4.
Fig. 4. Heparin binding site. A-C have the dimeric assemblage oriented as viewed from above Fig. 3A; B-D use the same color codes as in Fig. 3. (A) Electrostatic potential surface. Potential is graded from red ( ) to deep blue (>+16 kT). (B) Sulfate sites superimposed on the molecular surface. Sulfate ions in the surface channel of the complex are shown in yellow and sulfonate ions transformed from the FGF1:heparin structure (8) are in orange. (C) Heparin model (yellow) superimposed onto worm diagram. Six hexoses at each end are transformed directly from Ref. 8, and four in the middle are model built. Side chains of basic residues 176, 178, 208, and 210 are in purple. (D) End view of heparin superimposed onto worm. The view is rotated by 20° from Fig. 3A. Drawings were made by GRASP (37).
 
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
23403721 R.Goetz, and M.Mohammadi (2013).
Exploring mechanisms of FGF signalling through the lens of structural biology.
  Nat Rev Mol Cell Biol, 14, 166-180.  
20145243 I.S.Fernández, P.Cuevas, J.Angulo, P.López-Navajas, A.Canales-Mayordomo, R.González-Corrochano, R.M.Lozano, S.Valverde, J.Jiménez-Barbero, A.Romero, and G.Giménez-Gallego (2010).
Gentisic acid, a compound associated with plant defense and a metabolite of aspirin, heads a new class of in vivo fibroblast growth factor inhibitors.
  J Biol Chem, 285, 11714-11729.
PDB codes: 3jut 3k1x
  20596243 K.Raman, and B.Kuberan (2010).
Chemical Tumor Biology of Heparan Sulfate Proteoglycans.
  Curr Chem Biol, 4, 20-31.  
19658168 E.Stuttfeld, and K.Ballmer-Hofer (2009).
Structure and function of VEGF receptors.
  IUBMB Life, 61, 915-922.  
19564416 J.Kalinina, S.A.Byron, H.P.Makarenkova, S.K.Olsen, A.V.Eliseenkova, W.J.Larochelle, M.Dhanabal, S.Blais, D.M.Ornitz, L.A.Day, T.A.Neubert, P.M.Pollock, and M.Mohammadi (2009).
Homodimerization controls the fibroblast growth factor 9 subfamily's receptor binding and heparan sulfate-dependent diffusion in the extracellular matrix.
  Mol Cell Biol, 29, 4663-4678.
PDB code: 3f1r
19634127 S.Li, C.Christensen, L.B.Køhler, V.V.Kiselyov, V.Berezin, and E.Bock (2009).
Agonists of fibroblast growth factor receptor induce neurite outgrowth and survival of cerebellar granule neurons.
  Dev Neurobiol, 69, 837-854.  
18310252 P.Sharma, D.Rajalingam, T.K.Kumar, and S.Singh (2008).
A light scattering study of the interaction of fibroblast growth factor (FGF) with its receptor.
  Biophys J, 94, L71-L73.  
17460529 A.M.Parr, and C.H.Tator (2007).
Intrathecal epidermal growth factor and fibroblast growth factor-2 exacerbate meningeal proliferative lesions associated with intrathecal catheters.
  Neurosurgery, 60, 926.  
17525467 T.J.Kamerzell, S.B.Joshi, D.McClean, L.Peplinskie, K.Toney, D.Papac, M.Li, and C.R.Middaugh (2007).
Parathyroid hormone is a heparin/polyanion binding protein: binding energetics and structure modification.
  Protein Sci, 16, 1193-1203.  
16995857 A.Canales, R.Lozano, B.López-Méndez, J.Angulo, R.Ojeda, P.M.Nieto, M.Martín-Lomas, G.Giménez-Gallego, and J.Jiménez-Barbero (2006).
Solution NMR structure of a human FGF-1 monomer, activated by a hexasaccharide heparin-analogue.
  FEBS J, 273, 4716-4727.
PDB code: 2erm
16937240 A.Canales-Mayordomo, R.Fayos, J.Angulo, R.Ojeda, M.Martín-Pastor, P.M.Nieto, M.Martín-Lomas, R.Lozano, G.Giménez-Gallego, and J.Jiménez-Barbero (2006).
Backbone dynamics of a biologically active human FGF-1 monomer, complexed to a hexasaccharide heparin-analogue, by 15N NMR relaxation methods.
  J Biomol NMR, 35, 225-239.  
16955501 N.A.Oliveira, L.G.Alonso, R.D.Fanganiello, and M.R.Passos-Bueno (2006).
Further evidence of association between mutations in FGFR2 and syndromic craniosynostosis with sacrococcygeal eversion.
  Birth Defects Res A Clin Mol Teratol, 76, 629-633.  
16496021 P.Aloy, and R.B.Russell (2006).
Structural systems biology: modelling protein interactions.
  Nat Rev Mol Cell Biol, 7, 188-197.  
15715668 G.Williams, B.J.Eickholt, P.Maison, R.Prinjha, F.S.Walsh, and P.Doherty (2005).
A complementary peptide approach applied to the design of novel semaphorin/neuropilin antagonists.
  J Neurochem, 92, 1180-1190.  
15863029 M.Mohammadi, S.K.Olsen, and O.A.Ibrahimi (2005).
Structural basis for fibroblast growth factor receptor activation.
  Cytokine Growth Factor Rev, 16, 107-137.  
16154740 M.Mohammadi, S.K.Olsen, and R.Goetz (2005).
A protein canyon in the FGF-FGF receptor dimer selects from an à la carte menu of heparan sulfate motifs.
  Curr Opin Struct Biol, 15, 506-516.  
15632068 O.A.Ibrahimi, B.K.Yeh, A.V.Eliseenkova, F.Zhang, S.K.Olsen, M.Igarashi, S.A.Aaronson, R.J.Linhardt, and M.Mohammadi (2005).
Analysis of mutations in fibroblast growth factor (FGF) and a pathogenic mutation in FGF receptor (FGFR) provides direct evidence for the symmetric two-end model for FGFR dimerization.
  Mol Cell Biol, 25, 671-684.  
15973728 T.Nagayasu, S.Miyata, N.Hayashi, R.Takano, Y.Kariya, and K.Kamei (2005).
Heparin structures in FGF-2-dependent morphological transformation of astrocytes.
  J Biomed Mater Res A, 74, 374-380.  
14732692 S.K.Olsen, O.A.Ibrahimi, A.Raucci, F.Zhang, A.V.Eliseenkova, A.Yayon, C.Basilico, R.J.Linhardt, J.Schlessinger, and M.Mohammadi (2004).
Insights into the molecular basis for fibroblast growth factor receptor autoinhibition and ligand-binding promiscuity.
  Proc Natl Acad Sci U S A, 101, 935-940.
PDB code: 1ry7
12591959 B.K.Yeh, M.Igarashi, A.V.Eliseenkova, A.N.Plotnikov, I.Sher, D.Ron, S.A.Aaronson, and M.Mohammadi (2003).
Structural basis by which alternative splicing confers specificity in fibroblast growth factor receptors.
  Proc Natl Acad Sci U S A, 100, 2266-2271.
PDB code: 1nun
12949995 L.A.Kueltzo, and C.R.Middaugh (2003).
Nonclassical transport proteins and peptides: an alternative to classical macromolecule delivery systems.
  J Pharm Sci, 92, 1754-1772.  
14745970 X.Coumoul, and C.X.Deng (2003).
Roles of FGF receptors in mammalian development and congenital diseases.
  Birth Defects Res C Embryo Today, 69, 286-304.  
11967362 A.I.Arunkumar, T.K.Kumar, K.M.Kathir, S.Srisailam, H.M.Wang, P.S.Leena, Y.H.Chi, H.C.Chen, C.H.Wu, R.T.Wu, G.G.Chang, I.M.Chiu, and C.Yu (2002).
Oligomerization of acidic fibroblast growth factor is not a prerequisite for its cell proliferation activity.
  Protein Sci, 11, 1050-1061.  
12357470 A.O.Wilkie, S.J.Patey, S.H.Kan, A.M.van den Ouweland, and B.C.Hamel (2002).
FGFs, their receptors, and human limb malformations: clinical and molecular correlations.
  Am J Med Genet, 112, 266-278.  
12242295 B.K.Yeh, A.V.Eliseenkova, A.N.Plotnikov, D.Green, J.Pinnell, T.Polat, A.Gritli-Linde, R.J.Linhardt, and M.Mohammadi (2002).
Structural basis for activation of fibroblast growth factor signaling by sucrose octasulfate.
  Mol Cell Biol, 22, 7184-7192.  
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
12045103 J.D.Esko, and S.B.Selleck (2002).
Order out of chaos: assembly of ligand binding sites in heparan sulfate.
  Annu Rev Biochem, 71, 435-471.  
11847269 J.Kim, S.I.Blaber, and M.Blaber (2002).
Alternative type I and I' turn conformations in the beta8/beta9 beta-hairpin of human acidic fibroblast growth factor.
  Protein Sci, 11, 459-466.
PDB codes: 1k5u 1k5v
12461182 J.N.Varghese, R.L.Moritz, M.Z.Lou, A.Van Donkelaar, H.Ji, N.Ivancic, K.M.Branson, N.E.Hall, and R.J.Simpson (2002).
Structure of the extracellular domains of the human interleukin-6 receptor alpha -chain.
  Proc Natl Acad Sci U S A, 99, 15959-15964.
PDB codes: 1n26 1n2q
11972061 P.Aloy, and R.B.Russell (2002).
Interrogating protein interaction networks through structural biology.
  Proc Natl Acad Sci U S A, 99, 5896-5901.  
11781872 S.H.Kan, N.Elanko, D.Johnson, L.Cornejo-Roldan, J.Cook, E.W.Reich, S.Tomkins, A.Verloes, S.R.Twigg, S.Rannan-Eliya, D.M.McDonald-McGinn, E.H.Zackai, S.A.Wall, M.Muenke, and A.O.Wilkie (2002).
Genomic screening of fibroblast growth-factor receptor 2 reveals a wide spectrum of mutations in patients with syndromic craniosynostosis.
  Am J Hum Genet, 70, 472-486.  
11785765 B.Mulloy, and R.J.Linhardt (2001).
Order out of complexity--protein structures that interact with heparin.
  Curr Opin Struct Biol, 11, 623-628.  
11746231 C.Z.Borland, J.L.Schutzman, and M.J.Stern (2001).
Fibroblast growth factor signaling in Caenorhabditis elegans.
  Bioessays, 23, 1120-1130.  
11223514 H.J.Hecht, R.Adar, B.Hofmann, O.Bogin, H.Weich, and A.Yayon (2001).
Structure of fibroblast growth factor 9 shows a symmetric dimer with unique receptor- and heparin-binding interfaces.
  Acta Crystallogr D Biol Crystallogr, 57, 378-384.
PDB code: 1g82
  11457867 J.D.Esko, and U.Lindahl (2001).
Molecular diversity of heparan sulfate.
  J Clin Invest, 108, 169-173.  
11378392 J.Schoorlemmer, and M.Goldfarb (2001).
Fibroblast growth factor homologous factors are intracellular signaling proteins.
  Curr Biol, 11, 793-797.  
11785766 L.Pellegrini (2001).
Role of heparan sulfate in fibroblast growth factor signalling: a structural view.
  Curr Opin Struct Biol, 11, 629-634.  
11390973 O.A.Ibrahimi, A.V.Eliseenkova, A.N.Plotnikov, K.Yu, D.M.Ornitz, and M.Mohammadi (2001).
Structural basis for fibroblast growth factor receptor 2 activation in Apert syndrome.
  Proc Natl Acad Sci U S A, 98, 7182-7187.
PDB codes: 1ii4 1iil
11486033 P.Bellosta, A.Iwahori, A.N.Plotnikov, A.V.Eliseenkova, C.Basilico, and M.Mohammadi (2001).
Identification of receptor and heparin binding sites in fibroblast growth factor 4 by structure-based mutagenesis.
  Mol Cell Biol, 21, 5946-5957.
PDB code: 1ijt
10830168 A.N.Plotnikov, S.R.Hubbard, J.Schlessinger, and M.Mohammadi (2000).
Crystal structures of two FGF-FGFR complexes reveal the determinants of ligand-receptor specificity.
  Cell, 101, 413-424.
PDB codes: 1ev2 1evt
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.  
10978896 H.Kamiguchi, and V.Lemmon (2000).
IgCAMs: bidirectional signals underlying neurite growth.
  Curr Opin Cell Biol, 12, 598-605.  
10885578 I.McIntosh, G.A.Bellus, and E.W.Jab (2000).
The pleiotropic effects of fibroblast growth factor receptors in mammalian development.
  Cell Struct Funct, 25, 85-96.  
11042446 J.M.Rini, and N.Sharon (2000).
Glycosyltransferases, sugar nucleotide transporters and bacterial surface lectins - at the cutting edge of glycobiology
  Curr Opin Struct Biol, 10, 507-509.  
11030354 J.Schlessinger, A.N.Plotnikov, O.A.Ibrahimi, A.V.Eliseenkova, B.K.Yeh, A.Yayon, R.J.Linhardt, and M.Mohammadi (2000).
Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization.
  Mol Cell, 6, 743-750.
PDB code: 1fq9
11121055 K.Yu, A.B.Herr, G.Waksman, and D.M.Ornitz (2000).
Loss of fibroblast growth factor receptor 2 ligand-binding specificity in Apert syndrome.
  Proc Natl Acad Sci U S A, 97, 14536-14541.  
10753817 M.C.Deller, and E.Yvonne Jones (2000).
Cell surface receptors.
  Curr Opin Struct Biol, 10, 213-219.  
10945669 M.Priolo, M.Lerone, M.Baffico, M.Baldi, R.Ravazzolo, A.Cama, V.Capra, and M.Silengo (2000).
Pfeiffer syndrome type 2 associated with a single amino acid deletion in the FGFR2 gene.
  Clin Genet, 58, 81-83.  
11076027 T.L.Blundell, D.F.Burke, D.Chirgadze, V.Dhanaraj, M.Hyvönen, C.A.Innis, E.Parisini, L.Pellegrini, M.Sayed, and B.L.Sibanda (2000).
Protein-protein interactions in receptor activation and intracellular signalling.
  Biol Chem, 381, 955-959.  
10880433 X.Jiang, O.Gurel, E.A.Mendiaz, G.W.Stearns, C.L.Clogston, H.S.Lu, T.D.Osslund, R.S.Syed, K.E.Langley, and W.A.Hendrickson (2000).
Structure of the active core of human stem cell factor and analysis of binding to its receptor kit.
  EMBO J, 19, 3192-3203.
PDB code: 1scf
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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