title: Structure of the Tie2 RTK domain: self-inhibition by the nucleotide binding loop, activation loop, and C-terminal tail.
abstract: BACKGROUND
  Angiogenesis, the formation of new vessels from the existing vasculature, is a critical process during early development as well as in a number of disease processes. Tie2 (also known as Tek) is an endothelium-specific receptor tyrosine kinase involved in both angiogenesis and vasculature maintenance.
  
  
  RESULTS
  We have determined the crystal structure of the Tie2 kinase domain to 2.2 A resolution. The structure contains the catalytic core, the kinase insert domain (KID), and the C-terminal tail. The overall fold is similar to that observed in other serine/threonine and tyrosine kinase structures; however, several unique features distinguish the Tie2 structure from those of other kinases. The Tie2 nucleotide binding loop is in an inhibitory conformation, which is not seen in other kinase structures, while its activation loop adopts an "activated-like" conformation in the absence of phosphorylation. Tyr-897, located in the N-terminal domain, may negatively regulate the activity of Tie2 by preventing dimerization of the kinase domains or by recruiting phosphatases when it is phosphorylated.
  
  
  CONCLUSIONS
  Regulation of the kinase activity of Tie2 is a complex process. Conformational changes in the nucleotide binding loop, activation loop, C helix, and the C-terminal tail are required for ATP and substrate binding.
authors.affiliation: Glaxo Wellcome , Research Triangle Park, NC 27709, USA. lms18808@glaxowellcome.com
authors.forename: L M
authors.initials: LM
authors.lastname: Shewchuk
authors.forename: A M
authors.initials: AM
authors.lastname: Hassell
authors.forename: B
authors.initials: B
authors.lastname: Ellis
authors.forename: W D
authors.initials: WD
authors.lastname: Holmes
authors.forename: R
authors.initials: R
authors.lastname: Davis
authors.forename: E L
authors.initials: EL
authors.lastname: Horne
authors.forename: S H
authors.initials: SH
authors.lastname: Kadwell
authors.forename: D D
authors.initials: DD
authors.lastname: McKee
authors.forename: J T
authors.initials: JT
authors.lastname: Moore
mesh_terms: D019943:Amino Acid Substitution; D001808:Blood Vessels / Q000002:abnormalities; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D019281:Dimerization; D005799:Genes, Dominant; D006801:Humans; D006860:Hydrogen Bonding; D013058:Mass Spectrometry; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D042787:Receptor, TIE-2; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship; D018909:src Homology Domains
chemical_list: D011993:Recombinant Fusion Proteins; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2