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PDBsum entry 2py3

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protein ligands metals Protein-protein interface(s) links
Transferase PDB id
2py3
Jmol
Contents
Protein chains
282 a.a. *
Ligands
SO4 ×4
ACP ×2
Metals
_MG ×4
Waters ×172
* Residue conservation analysis
PDB id:
2py3
Name: Transferase
Title: Crystal strucure of fgf receptor 2 (fgfr2) kinase domain har pathogenic e565g mutation responsible for pfeiffer syndrome
Structure: Fibroblast growth factor receptor 2. Chain: a, b. Fragment: kinase domain. Synonym: fgfr-2, keratinocyte growth factor receptor 2, cd3 antigen. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: fgfr2, bek, ksam. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.30Å     R-factor:   0.217     R-free:   0.252
Authors: H.Chen,M.Mohammadi
Key ref:
H.Chen et al. (2007). A molecular brake in the kinase hinge region regulates the activity of receptor tyrosine kinases. Mol Cell, 27, 717-730. PubMed id: 17803937 DOI: 10.1016/j.molcel.2007.06.028
Date:
15-May-07     Release date:   25-Sep-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P21802  (FGFR2_HUMAN) -  Fibroblast growth factor receptor 2
Seq:
Struc:
 
Seq:
Struc:
821 a.a.
282 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.2.7.10.1  - Receptor protein-tyrosine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate
ATP
+ [protein]-L-tyrosine
=
ADP
Bound ligand (Het Group name = ACP)
matches with 81.25% similarity
+ [protein]-L-tyrosine phosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     signal transduction   6 terms 
  Biochemical function     transferase activity, transferring phosphorus-containing groups     6 terms  

 

 
    reference    
 
 
DOI no: 10.1016/j.molcel.2007.06.028 Mol Cell 27:717-730 (2007)
PubMed id: 17803937  
 
 
A molecular brake in the kinase hinge region regulates the activity of receptor tyrosine kinases.
H.Chen, J.Ma, W.Li, A.V.Eliseenkova, C.Xu, T.A.Neubert, W.T.Miller, M.Mohammadi.
 
  ABSTRACT  
 
Activating mutations in the tyrosine kinase domain of receptor tyrosine kinases (RTKs) cause cancer and skeletal disorders. Comparison of the crystal structures of unphosphorylated and phosphorylated wild-type FGFR2 kinase domains with those of seven unphosphorylated pathogenic mutants reveals an autoinhibitory "molecular brake" mediated by a triad of residues in the kinase hinge region of all FGFRs. Structural analysis shows that many other RTKs, including PDGFRs, VEGFRs, KIT, CSF1R, FLT3, TEK, and TIE, are also subject to regulation by this brake. Pathogenic mutations activate FGFRs and other RTKs by disengaging the brake either directly or indirectly.
 
  Selected figure(s)  
 
Figure 3.
Figure 3. The Molecular Brake at the Kinase Hinge Region of FGFR2K Regulates the Kinase Activation and Is Disengaged Either by A Loop Tyrosine Phosphorylation or Directly by the Pathogenic Mutations
(A) In the unphosphorylated wild-type structure, residues N549, E565, and K641 form a network of hydrogen bonds in the kinase hinge region, which serves as a molecular brake to keep the enzyme in an inactive state.
(B) The molecular brake is disengaged in the A loop tyrosine phosphorylated wild-type FGFR2K structure. This molecular brake is also disengaged in the unphosphorylated mutant FGFR2K structures (C–G). To assist the readers, the whole unphosphorylated wild-type FGFR2K structure is also shown in cartoon and solid semitransparent surface, and the kinase hinge region is boxed. Atom colorings are as follows: oxygens in red, nitrogens in blue, and carbons are colored according to the kinase region to which they belong. The kinase hinge, the αC-β4 loop (shown in sticks in [A]–[G]), and β8 strand are colored green, wheat, and cyan, respectively. The rest of the N lobe and C lobe is colored light purple and light blue, respectively. The three critical hydrogen bonds between N549 and the backbone atoms of αC-β4 loop are highlighted by red dashed lines. The remaining hydrogen bonds are shown as black dashed lines.
Figure 6.
Figure 6. The Autoinhibition by the Molecular Brake Is a Common Regulatory Mechanism for Many RTKs
(A)–(E) show the presence of the engaged molecular brake at the kinase hinge region of unphosphorylated wild-type FGFR1 (PDB ID: 1FGK), CSF1R (PDB ID: 2I1M), VEGFR2 (PDB ID: 1VR2), TEK (PDB ID: 1FVR), and c-KIT (PDB ID: 1T45) kinases, respectively. (F) shows the disengagement of the molecular brake at the kinase hinge region of an “active” c-KIT kinase (PDB ID: 1PKG). Coloring scheme is as in Figure 3.
 
  The above figures are reprinted from an Open Access publication published by Cell Press: Mol Cell (2007, 27, 717-730) copyright 2007.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21367659 H.Greulich, and P.M.Pollock (2011).
Targeting mutant fibroblast growth factor receptors in cancer.
  Trends Mol Med, 17, 283-292.  
20564212 C.R.Degnin, M.B.Laederich, and W.A.Horton (2010).
FGFs in endochondral skeletal development.
  J Cell Biochem, 110, 1046-1057.  
21119733 F.Grimminger, R.T.Schermuly, and H.A.Ghofrani (2010).
Targeting non-malignant disorders with tyrosine kinase inhibitors.
  Nat Rev Drug Discov, 9, 956-970.  
20432069 J.H.Bae, and J.Schlessinger (2010).
Asymmetric tyrosine kinase arrangements in activation or autophosphorylation of receptor tyrosine kinases.
  Mol Cells, 29, 443-448.  
20601886 M.B.Laederich, and W.A.Horton (2010).
Achondroplasia: pathogenesis and implications for future treatment.
  Curr Opin Pediatr, 22, 516-523.  
20336234 O.A.Gani, and R.A.Engh (2010).
Protein kinase inhibition of clinically important staurosporine analogues.
  Nat Prod Rep, 27, 489-498.  
20503384 S.Mai, K.Wei, A.Flenniken, S.L.Adamson, J.Rossant, J.E.Aubin, and S.G.Gong (2010).
The missense mutation W290R in Fgfr2 causes developmental defects from aberrant IIIb and IIIc signaling.
  Dev Dyn, 239, 1888-1900.  
19247306 A.Beenken, and M.Mohammadi (2009).
The FGF family: biology, pathophysiology and therapy.
  Nat Rev Drug Discov, 8, 235-253.  
19855393 A.Goriely, R.M.Hansen, I.B.Taylor, I.A.Olesen, G.K.Jacobsen, S.J.McGowan, S.P.Pfeifer, G.A.McVean, E.R.Meyts, and A.O.Wilkie (2009).
Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors.
  Nat Genet, 41, 1247-1252.  
19290920 B.B.Au-Yeung, S.Deindl, L.Y.Hsu, E.H.Palacios, S.E.Levin, J.Kuriyan, and A.Weiss (2009).
The structure, regulation, and function of ZAP-70.
  Immunol Rev, 228, 41-57.  
19273857 D.J.Kemble, and G.Sun (2009).
Direct and specific inactivation of protein tyrosine kinases in the Src and FGFR families by reversible cysteine oxidation.
  Proc Natl Acad Sci U S A, 106, 5070-5075.  
19224897 E.D.Lew, C.M.Furdui, K.S.Anderson, and J.Schlessinger (2009).
The precise sequence of FGF receptor autophosphorylation is kinetically driven and is disrupted by oncogenic mutations.
  Sci Signal, 2, ra6.  
18726952 E.G.Bochukova, T.Roscioli, D.J.Hedges, I.B.Taylor, D.Johnson, D.J.David, P.L.Deininger, and A.O.Wilkie (2009).
Rare mutations of FGFR2 causing apert syndrome: identification of the first partial gene deletion, and an Alu element insertion from a new subfamily.
  Hum Mutat, 30, 204-211.  
  19809159 J.G.Taylor, A.T.Cheuk, P.S.Tsang, J.Y.Chung, Y.K.Song, K.Desai, Y.Yu, Q.R.Chen, K.Shah, V.Youngblood, J.Fang, S.Y.Kim, C.Yeung, L.J.Helman, A.Mendoza, V.Ngo, L.M.Staudt, J.S.Wei, C.Khanna, D.Catchpoole, S.J.Qualman, S.M.Hewitt, G.Merlino, S.J.Chanock, and J.Khan (2009).
Identification of FGFR4-activating mutations in human rhabdomyosarcomas that promote metastasis in xenotransplanted models.
  J Clin Invest, 119, 3395-3407.  
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
19387476 M.Katoh (2009).
FGFR2 abnormalities underlie a spectrum of bone, skin, and cancer pathologies.
  J Invest Dermatol, 129, 1861-1867.  
19563760 N.Jura, N.F.Endres, K.Engel, S.Deindl, R.Das, M.H.Lamers, D.E.Wemmer, X.Zhang, and J.Kuriyan (2009).
Mechanism for activation of the EGF receptor catalytic domain by the juxtamembrane segment.
  Cell, 137, 1293-1307.
PDB code: 3gt8
19077689 P.A.Insel, and H.H.Patel (2009).
Membrane rafts and caveolae in cardiovascular signaling.
  Curr Opin Nephrol Hypertens, 18, 50-56.  
19429619 P.G.Young, R.Walanj, V.Lakshmi, L.J.Byrnes, P.Metcalf, E.N.Baker, S.B.Vakulenko, and C.A.Smith (2009).
The crystal structures of substrate and nucleotide complexes of Enterococcus faecium aminoglycoside-2''-phosphotransferase-IIa [APH(2'')-IIa] provide insights into substrate selectivity in the APH(2'') subfamily.
  J Bacteriol, 191, 4133-4143.
PDB codes: 3ham 3hav
19243295 S.A.Byron, and P.M.Pollock (2009).
FGFR2 as a molecular target in endometrial cancer.
  Future Oncol, 5, 27-32.  
19449430 S.Pannier, J.Martinovic, S.Heuertz, A.L.Delezoide, A.Munnich, L.Schibler, V.Serre, and L.Legeai-Mallet (2009).
Thanatophoric dysplasia caused by double missense FGFR3 mutations.
  Am J Med Genet A, 149, 1296-1301.  
19716710 W.A.Horton, and C.R.Degnin (2009).
FGFs in endochondral skeletal development.
  Trends Endocrinol Metab, 20, 341-348.  
18552176 A.Dutt, H.B.Salvesen, T.H.Chen, A.H.Ramos, R.C.Onofrio, C.Hatton, R.Nicoletti, W.Winckler, R.Grewal, M.Hanna, N.Wyhs, L.Ziaugra, D.J.Richter, J.Trovik, I.B.Engelsen, I.M.Stefansson, T.Fennell, K.Cibulskis, M.C.Zody, L.A.Akslen, S.Gabriel, K.K.Wong, W.R.Sellers, M.Meyerson, and H.Greulich (2008).
Drug-sensitive FGFR2 mutations in endometrial carcinoma.
  Proc Natl Acad Sci U S A, 105, 8713-8717.  
19060208 H.Chen, C.F.Xu, J.Ma, A.V.Eliseenkova, W.Li, P.M.Pollock, N.Pitteloud, W.T.Miller, T.A.Neubert, and M.Mohammadi (2008).
A crystallographic snapshot of tyrosine trans-phosphorylation in action.
  Proc Natl Acad Sci U S A, 105, 19660-19665.
PDB code: 3cly
18948947 L.Ding, G.Getz, D.A.Wheeler, E.R.Mardis, M.D.McLellan, K.Cibulskis, C.Sougnez, H.Greulich, D.M.Muzny, M.B.Morgan, L.Fulton, R.S.Fulton, Q.Zhang, M.C.Wendl, M.S.Lawrence, D.E.Larson, K.Chen, D.J.Dooling, A.Sabo, A.C.Hawes, H.Shen, S.N.Jhangiani, L.R.Lewis, O.Hall, Y.Zhu, T.Mathew, Y.Ren, J.Yao, S.E.Scherer, K.Clerc, G.A.Metcalf, B.Ng, A.Milosavljevic, M.L.Gonzalez-Garay, J.R.Osborne, R.Meyer, X.Shi, Y.Tang, D.C.Koboldt, L.Lin, R.Abbott, T.L.Miner, C.Pohl, G.Fewell, C.Haipek, H.Schmidt, B.H.Dunford-Shore, A.Kraja, S.D.Crosby, C.S.Sawyer, T.Vickery, S.Sander, J.Robinson, W.Winckler, J.Baldwin, L.R.Chirieac, A.Dutt, T.Fennell, M.Hanna, B.E.Johnson, R.C.Onofrio, R.K.Thomas, G.Tonon, B.A.Weir, X.Zhao, L.Ziaugra, M.C.Zody, T.Giordano, M.B.Orringer, J.A.Roth, M.R.Spitz, I.I.Wistuba, B.Ozenberger, P.J.Good, A.C.Chang, D.G.Beer, M.A.Watson, M.Ladanyi, S.Broderick, A.Yoshizawa, W.D.Travis, W.Pao, M.A.Province, G.M.Weinstock, H.E.Varmus, S.B.Gabriel, E.S.Lander, R.A.Gibbs, M.Meyerson, and R.K.Wilson (2008).
Somatic mutations affect key pathways in lung adenocarcinoma.
  Nature, 455, 1069-1075.  
18812319 Y.Ohne, T.Takahara, R.Hatakeyama, T.Matsuzaki, M.Noda, N.Mizushima, and T.Maeda (2008).
Isolation of hyperactive mutants of mammalian target of rapamycin.
  J Biol Chem, 283, 31861-31870.  
18056630 E.D.Lew, J.H.Bae, E.Rohmann, B.Wollnik, and J.Schlessinger (2007).
Structural basis for reduced FGFR2 activity in LADD syndrome: Implications for FGFR autoinhibition and activation.
  Proc Natl Acad Sci U S A, 104, 19802-19807.
PDB code: 3b2t
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.