PDBsum entry 2p2i

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Transferase PDB id
Protein chains
289 a.a. *
263 a.a. *
608 ×2
Waters ×122
* Residue conservation analysis
PDB id:
Name: Transferase
Title: Crystal structure of the vegfr2 kinase domain in complex with a nicotinamide inhibitor
Structure: Vascular endothelial growth factor receptor 2. Chain: a, b. Fragment: kinase domain. Synonym: vegfr-2, kinase insert domain receptor, protein- tyrosine kinase receptor flk-1, cd309 antigen. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: kdr, flk1. Expressed in: trichoplusia ni. Expression_system_taxid: 7111.
2.40Å     R-factor:   0.222     R-free:   0.266
Authors: D.A.Whittington,J.L.Kim,A.M.Long,P.Rose,Y.Gu,H.Zhao
Key ref: B.L.Hodous et al. (2007). Evolution of a highly selective and potent 2-(pyridin-2-yl)-1,3,5-triazine Tie-2 kinase inhibitor. J Med Chem, 50, 611-626. PubMed id: 17253678 DOI: 10.1021/jm061107l
07-Mar-07     Release date:   20-Mar-07    
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Protein chain
Pfam   ArchSchema ?
P35968  (VGFR2_HUMAN) -  Vascular endothelial growth factor receptor 2
1356 a.a.
289 a.a.*
Protein chain
Pfam   ArchSchema ?
P35968  (VGFR2_HUMAN) -  Vascular endothelial growth factor receptor 2
1356 a.a.
263 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 9 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: Chains A, B: E.C.  - Receptor protein-tyrosine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate
+ [protein]-L-tyrosine
+ [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   2 terms 
  Biological process     transmembrane receptor protein tyrosine kinase signaling pathway   3 terms 
  Biochemical function     transferase activity, transferring phosphorus-containing groups     7 terms  


DOI no: 10.1021/jm061107l J Med Chem 50:611-626 (2007)
PubMed id: 17253678  
Evolution of a highly selective and potent 2-(pyridin-2-yl)-1,3,5-triazine Tie-2 kinase inhibitor.
B.L.Hodous, S.D.Geuns-Meyer, P.E.Hughes, B.K.Albrecht, S.Bellon, J.Bready, S.Caenepeel, V.J.Cee, S.C.Chaffee, A.Coxon, M.Emery, J.Fretland, P.Gallant, Y.Gu, D.Hoffman, R.E.Johnson, R.Kendall, J.L.Kim, A.M.Long, M.Morrison, P.R.Olivieri, V.F.Patel, A.Polverino, P.Rose, P.Tempest, L.Wang, D.A.Whittington, H.Zhao.
Inhibition of angiogenesis is a promising and clinically validated approach for limiting tumor growth and survival. The receptor tyrosine kinase Tie-2 is expressed almost exclusively in the vascular endothelium and is required for developmental angiogenesis and vessel maturation. However, the significance of Tie-2 signaling in tumor angiogenesis is not well understood. In order to evaluate the therapeutic utility of inhibiting Tie-2 signaling, we developed a series of potent and orally bioavailable small molecule Tie-2 kinase inhibitors with selectivity over other kinases, especially those that are believed to be important for tumor angiogenesis. Our earlier work provided pyridinyl pyrimidine 6 as a potent, nonselective Tie-2 inhibitor that was designed on the basis of X-ray cocrystal structures of KDR inhibitors 34 (triazine) and 35 (nicotinamide). Lead optimization resulted in pyridinyl triazine 63, which exhibited >30-fold selectivity over a panel of kinases, good oral exposure, and in vivo inhibition of Tie-2 phosphorylation.

Literature references that cite this PDB file's key reference

  PubMed id Reference
19921722 A.Papakyriakou, M.E.Katsarou, M.Belimezi, M.Karpusas, and D.Vourloumis (2010).
Discovery of potent vascular endothelial growth factor receptor-2 inhibitors.
  ChemMedChem, 5, 118-129.  
20189109 P.Ranjitkar, A.M.Brock, and D.J.Maly (2010).
Affinity reagents that target a specific inactive form of protein kinases.
  Chem Biol, 17, 195-206.  
19234476 H.G.Augustin, G.Young Koh, G.Thurston, and K.Alitalo (2009).
Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system.
  Nat Rev Mol Cell Biol, 10, 165-177.  
19276351 M.A.Seeliger, P.Ranjitkar, C.Kasap, Y.Shan, D.E.Shaw, N.P.Shah, J.Kuriyan, and D.J.Maly (2009).
Equally potent inhibition of c-Src and Abl by compounds that recognize inactive kinase conformations.
  Cancer Res, 69, 2384-2392.
PDB codes: 3g6g 3g6h
19471858 M.H.Seifert (2009).
Robust optimization of scoring functions for a target class.
  J Comput Aided Mol Des, 23, 633-644.  
19449109 M.Thomas, and H.G.Augustin (2009).
The role of the Angiopoietins in vascular morphogenesis.
  Angiogenesis, 12, 125-137.  
18183356 I.J.Enyedy, and W.J.Egan (2008).
Can we use docking and scoring for hit-to-lead optimization?
  J Comput Aided Mol Des, 22, 161-168.  
18055465 S.F.Bellon, P.Kaplan-Lefko, Y.Yang, Y.Zhang, J.Moriguchi, K.Rex, C.W.Johnson, P.E.Rose, A.M.Long, A.B.O'Connor, Y.Gu, A.Coxon, T.S.Kim, A.Tasker, T.L.Burgess, and I.Dussault (2008).
c-Met Inhibitors with Novel Binding Mode Show Activity against Several Hereditary Papillary Renal Cell Carcinoma-related Mutations.
  J Biol Chem, 283, 2675-2683.
PDB codes: 2rfn 2rfs
18266978 T.Makinde, and D.K.Agrawal (2008).
Intra and extravascular transmembrane signalling of angiopoietin-1-Tie2 receptor in health and disease.
  J Cell Mol Med, 12, 810-828.  
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.