PDBsum entry 2cew

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protein links
Transferase PDB id
Protein chain
272 a.a.
Theoretical model
PDB id:
Name: Transferase
Title: 3d structure prediction of the ig2-ig4 domains of the ectodomain region of the human hepatocyte growth factor- scatter factor receptor, met
Structure: Hepatocyte growth factor receptor. Synonym: hepatocyte growth factor-scatter factor receptor, met proto-oncogene tyrosine kinase, c-met, hgf receptor, hgf-sf receptor. Chain: a. Fragment: ig2-ig4 domains, residues 657-928. Ec:
Source: Synthetic: yes. Homo sapiens. Human
Authors: R.N.Miguel,T.L.Blundell,E.Gherardi
Key ref:
E.Gherardi et al. (2006). Structural basis of hepatocyte growth factor/scatter factor and MET signalling. Proc Natl Acad Sci U S A, 103, 4046-4051. PubMed id: 16537482 DOI: 10.1073/pnas.0509040103
10-Feb-06     Release date:   21-Feb-06    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P08581  (MET_HUMAN) -  Hepatocyte growth factor receptor
1390 a.a.
272 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure

 Enzyme reactions 
   Enzyme class: E.C.  - Transferred entry: and
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein tyrosine = ADP + protein tyrosine phosphate

+ a
Molecule diagrams generated from .mol files obtained from the KEGG ftp site


DOI no: 10.1073/pnas.0509040103 Proc Natl Acad Sci U S A 103:4046-4051 (2006)
PubMed id: 16537482  
Structural basis of hepatocyte growth factor/scatter factor and MET signalling.
E.Gherardi, S.Sandin, M.V.Petoukhov, J.Finch, M.E.Youles, L.G.Ofverstedt, R.N.Miguel, T.L.Blundell, G.F.Vande Woude, U.Skoglund, D.I.Svergun.
The polypeptide growth factor, hepatocyte growth factor/scatter factor (HGF/SF), shares the multidomain structure and proteolytic mechanism of activation of plasminogen and other complex serine proteinases. HGF/SF, however, has no enzymatic activity. Instead, it controls the growth, morphogenesis, or migration of epithelial, endothelial, and muscle progenitor cells through the receptor tyrosine kinase MET. Using small-angle x-ray scattering and cryo-electron microscopy, we show that conversion of pro(single-chain)HGF/SF into the active two-chain form is associated with a major structural transition from a compact, closed conformation to an elongated, open one. We also report the structure of a complex between two-chain HGF/SF and the MET ectodomain (MET928) with 1:1 stoichiometry in which the N-terminal and first kringle domain of HGF/SF contact the face of the seven-blade beta-propeller domain of MET harboring the loops connecting the beta-strands b-c and d-a, whereas the C-terminal serine proteinase homology domain binds the opposite "b" face. Finally, we describe a complex with 2:2 stoichiometry between two-chain HGF/SF and a truncated form of the MET ectodomain (MET567), which is assembled around the dimerization interface seen in the crystal structure of the NK1 fragment of HGF/SF and displays the features of a functional, signaling unit. The study shows how the proteolytic mechanism of activation of the complex proteinases has been adapted to cell signaling in vertebrate organisms, offers a description of monomeric and dimeric ligand-receptor complexes, and provides a foundation to the structural basis of HGF/SF-MET signaling.
  Selected figure(s)  
Figure 1.
Fig. 1. Domain structure and biological activity of the three main proteins used in this study. (A) Domain structure. (B) SDS/PAGE under reducing conditions. (C–E) Typical appearance of colonies of MDCK cells under standard culture conditions (C) or after addition of single-chain (D) or two-chain (E) HGF/SF at the concentrations indicated. sc-SF, single HGF/SF; tc-SF, two-chain HGF/SF.
Figure 4.
Fig. 4. The 1:1 complex formed by two-chain HGF/SF and MET928. (A and B) SAXS of the two-chain HGF/SF-MET928 complex. (A) Scattering curve and ab initio model (28). (B) Rigid body model (29) (MET928 in gray, two-chain HGF/SF in red). (C–K) CET of the two-chain HGF/SF-MET928 complex. (C–E) Three views of a typical 3D reconstruction. (F–H) Corresponding images after low pass filtering. (I–K) Docking of the SAXS model of the two-chain HGF/SF-MET928 complex into the EM density envelope (MET -propeller in blue; sp domain of HGF/SF in green; other HGF/SF domains in yellow); sc-SF, single-chain HGF/SF; tc-SF, two-chain HGF/SF.
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
22270953 E.Gherardi, W.Birchmeier, C.Birchmeier, and G.Vande Woude (2012).
Targeting MET in cancer: rationale and progress.
  Nat Rev Cancer, 12, 89.  
20648549 O.Rho, D.J.Kim, K.Kiguchi, and J.Digiovanni (2011).
Growth factor signaling pathways as targets for prevention of epithelial carcinogenesis.
  Mol Carcinog, 50, 264-279.  
20977569 O.Steele-Mortimer (2011).
Exploitation of the ubiquitin system by invading bacteria.
  Traffic, 12, 162-169.  
21217780 R.Szabo, A.L.Rasmussen, A.B.Moyer, P.Kosa, J.M.Schafer, A.A.Molinolo, J.S.Gutkind, and T.H.Bugge (2011).
c-Met-induced epithelial carcinogenesis is initiated by the serine protease matriptase.
  Oncogene, 30, 2003-2016.  
20603611 A.R.Cantelmo, R.Cammarota, D.M.Noonan, C.Focaccetti, P.M.Comoglio, M.Prat, and A.Albini (2010).
Cell delivery of Met docking site peptides inhibit angiogenesis and vascular tumor growth.
  Oncogene, 29, 5286-5298.  
20877282 B.J.Janssen, R.A.Robinson, F.Pérez-Brangulí, C.H.Bell, K.J.Mitchell, C.Siebold, and E.Y.Jones (2010).
Structural basis of semaphorin-plexin signalling.
  Nature, 467, 1118-1122.
PDB codes: 3okt 3okw 3oky 3ol2
20086056 B.J.Yamamoto, P.D.Elias, J.A.Masino, B.D.Hudson, A.T.McCoy, Z.J.Anderson, M.D.Varnum, M.F.Sardinia, J.W.Wright, and J.W.Harding (2010).
The angiotensin IV analog Nle-Tyr-Leu-psi-(CH2-NH2)3-4-His-Pro-Phe (norleual) can act as a hepatocyte growth factor/c-Met inhibitor.
  J Pharmacol Exp Ther, 333, 161-173.  
20536384 H.R.Maun, D.Kirchhofer, and R.A.Lazarus (2010).
Pseudo-active sites of protease domains: HGF/Met and Sonic hedgehog signaling in cancer.
  Biol Chem, 391, 881-892.  
20015050 K.A.Owen, D.Qiu, J.Alves, A.M.Schumacher, L.M.Kilpatrick, J.Li, J.L.Harris, and V.Ellis (2010).
Pericellular activation of hepatocyte growth factor by the transmembrane serine proteases matriptase and hepsin, but not by the membrane-associated protease uPA.
  Biochem J, 426, 219-228.  
20639469 R.Sinha Roy, S.Soni, R.Harfouche, P.R.Vasudevan, O.Holmes, Jonge, A.Rowe, A.Paraskar, D.M.Hentschel, D.Chirgadze, T.L.Blundell, E.Gherardi, R.A.Mashelkar, and S.Sengupta (2010).
Coupling growth-factor engineering with nanotechnology for therapeutic angiogenesis.
  Proc Natl Acad Sci U S A, 107, 13608-13613.  
20512979 S.Wilke, J.Krausze, M.Gossen, L.Groebe, V.Jäger, E.Gherardi, J.van den Heuvel, and K.Büssow (2010).
Glycoprotein production for structure analysis with stable, glycosylation mutant CHO cell lines established by fluorescence-activated cell sorting.
  Protein Sci, 19, 1264-1271.  
20624990 W.D.Tolbert, J.Daugherty-Holtrop, E.Gherardi, G.Vande Woude, and H.E.Xu (2010).
Structural basis for agonism and antagonism of hepatocyte growth factor.
  Proc Natl Acad Sci U S A, 107, 13264-13269.
PDB codes: 3hmr 3hms 3hmt 3hn4
19758803 A.Z.Lai, J.V.Abella, and M.Park (2009).
Crosstalk in Met receptor oncogenesis.
  Trends Cell Biol, 19, 542-551.  
19861420 E.Y.Bugaeva, S.Surkov, A.V.Golovin, L.G.Ofverstedt, U.Skoglund, L.A.Isaksson, A.A.Bogdanov, O.V.Shpanchenko, and O.A.Dontsova (2009).
Structural features of the tmRNA-ribosome interaction.
  RNA, 15, 2312-2320.  
19939254 H.E.Crosswell, A.Dasgupta, C.S.Alvarado, T.Watt, J.G.Christensen, P.De, D.L.Durden, and H.W.Findley (2009).
PHA665752, a small-molecule inhibitor of c-Met, inhibits hepatocyte growth factor-stimulated migration and proliferation of c-Met-positive neuroblastoma cells.
  BMC Cancer, 9, 411.  
19710186 M.Müller, K.Richter, A.Heuck, E.Kremmer, J.Buchner, R.P.Jansen, and D.Niessing (2009).
Formation of She2p tetramers is required for mRNA binding, mRNP assembly, and localization.
  RNA, 15, 2002-2012.  
  20368753 M.Sattler, and R.Salgia (2009).
The MET axis as a therapeutic target.
  Update Cancer Ther, 3, 109-118.  
  19389925 N.Buchstein, D.Hoffmann, H.Smola, S.Lang, M.Paulsson, C.Niemann, T.Krieg, and S.A.Eming (2009).
Alternative proteolytic processing of hepatocyte growth factor during wound repair.
  Am J Pathol, 174, 2116-2128.  
19415747 T.G.Wright, V.K.Singh, J.J.Li, J.H.Foley, F.Miller, Z.Jia, and B.E.Elliott (2009).
Increased production and secretion of HGF alpha-chain and an antagonistic HGF fragment in a human breast cancer progression model.
  Int J Cancer, 125, 1004-1015.  
18495663 C.Basilico, A.Arnesano, M.Galluzzo, P.M.Comoglio, and P.Michieli (2008).
A high affinity hepatocyte growth factor-binding site in the immunoglobulin-like region of Met.
  J Biol Chem, 283, 21267-21277.  
18078545 C.D.Putnam, M.Hammel, G.L.Hura, and J.A.Tainer (2007).
X-ray solution scattering (SAXS) combined with crystallography and computation: defining accurate macromolecular structures, conformations and assemblies in solution.
  Q Rev Biophys, 40, 191-285.  
17372204 D.Kirchhofer, M.T.Lipari, L.Santell, K.L.Billeci, H.R.Maun, W.N.Sandoval, P.Moran, J.Ridgway, C.Eigenbrot, and R.A.Lazarus (2007).
Utilizing the activation mechanism of serine proteases to engineer hepatocyte growth factor into a Met antagonist.
  Proc Natl Acad Sci U S A, 104, 5306-5311.  
17662939 H.H.Niemann, V.Jäger, P.J.Butler, J.van den Heuvel, S.Schmidt, D.Ferraris, E.Gherardi, and D.W.Heinz (2007).
Structure of the human receptor tyrosine kinase met in complex with the Listeria invasion protein InlB.
  Cell, 130, 235-246.
PDB codes: 2uzx 2uzy
17118400 J.Lipfert, R.Das, V.B.Chu, M.Kudaravalli, N.Boyd, D.Herschlag, and S.Doniach (2007).
Structural transitions and thermodynamics of a glycine-dependent riboswitch from Vibrio cholerae.
  J Mol Biol, 365, 1393-1406.  
17284163 J.Lipfert, and S.Doniach (2007).
Small-angle X-ray scattering from RNA, proteins, and protein complexes.
  Annu Rev Biophys Biomol Struct, 36, 307-327.  
17419717 K.Ireton (2007).
Entry of the bacterial pathogen Listeria monocytogenes into mammalian cells.
  Cell Microbiol, 9, 1365-1375.  
17288874 M.Sattler, and R.Salgia (2007).
c-Met and hepatocyte growth factor: potential as novel targets in cancer therapy.
  Curr Oncol Rep, 9, 102-108.  
17306972 S.R.Hubbard, and W.T.Miller (2007).
Receptor tyrosine kinases: mechanisms of activation and signaling.
  Curr Opin Cell Biol, 19, 117-123.  
17804794 W.D.Tolbert, J.Daugherty, C.Gao, Q.Xie, C.Miranti, E.Gherardi, G.V.Woude, and H.E.Xu (2007).
A mechanistic basis for converting a receptor tyrosine kinase agonist to an antagonist.
  Proc Natl Acad Sci U S A, 104, 14592-14597.
PDB codes: 2qj2 2qj4
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.