PMID- 10368301
OWN - NLM
STAT- MEDLINE
DCOM- 19990506
LR  - 20190915
IS  - 0969-2126 (Print)
IS  - 0969-2126 (Linking)
VI  - 7
IP  - 3
DP  - 1999 Mar 15
TI  - Crystal structure of the kinase domain of human vascular endothelial growth
      factor receptor 2: a key enzyme in angiogenesis.
PG  - 319-30
AB  - BACKGROUND: Angiogenesis is involved in tumor growth, macular degeneration,
      retinopathy and other diseases. Vascular endothelial growth factor (VEGF)
      stimulates angiogenesis by binding to specific receptors (VEGFRs) on the surface 
      of vascular endothelial cells. VEGFRs are receptor tyrosine kinases that, like
      the platelet-derived growth factor receptors (PDGFRs), contain a large insert
      within the kinase domain. RESULTS: We report here the generation, kinetic
      characterization, and 2.4 A crystal structure of the catalytic kinase domain of
      VEGF receptor 2 (VEGFR2). This protein construct, which lacks 50 central residues
      of the 68-residue kinase insert domain (KID), has comparable kinase activity to
      constructs containing the entire KID. The crystal structure, determined in an
      unliganded phosphorylated state, reveals an overall fold and catalytic residue
      positions similar to those observed in other tyrosine-kinase structures. The
      kinase activation loop, autophosphorylated on Y1059 prior to crystallization, is 
      mostly disordered; however, a portion of it occupies a position inhibitory to
      substrate binding. The ends of the KID form a beta-like structure, not observed
      in other known tyrosine kinase structures, that packs near to the kinase C
      terminus. CONCLUSIONS: The majority of the VEGFR2 KID residues are not necessary 
      for kinase activity. The unique structure observed for the ends of the KID may
      also occur in other PDGFR family members and may serve to properly orient the KID
      for signal transduction. This VEGFR2 kinase structure provides a target for
      design of selective anti-angiogenic therapeutic agents.
FAU - McTigue, M A
AU  - McTigue MA
AD  - Agouron Pharmaceuticals, 3565 General Atomics Court, San Diego, CA 92121, USA.
      mctigue@agouron.com
FAU - Wickersham, J A
AU  - Wickersham JA
FAU - Pinko, C
AU  - Pinko C
FAU - Showalter, R E
AU  - Showalter RE
FAU - Parast, C V
AU  - Parast CV
FAU - Tempczyk-Russell, A
AU  - Tempczyk-Russell A
FAU - Gehring, M R
AU  - Gehring MR
FAU - Mroczkowski, B
AU  - Mroczkowski B
FAU - Kan, C C
AU  - Kan CC
FAU - Villafranca, J E
AU  - Villafranca JE
FAU - Appelt, K
AU  - Appelt K
LA  - eng
SI  - PDB/1VR2
PT  - Comparative Study
PT  - Journal Article
PL  - United States
TA  - Structure
JT  - Structure (London, England : 1993)
JID - 101087697
RN  - 0 (Growth Substances)
RN  - 0 (Peptide Fragments)
RN  - 0 (Receptors, Growth Factor)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
RN  - EC 2.7.10.1 (Receptors, Vascular Endothelial Growth Factor)
SB  - IM
MH  - Adenosine Triphosphate/metabolism
MH  - Amino Acid Sequence
MH  - Binding Sites
MH  - Catalytic Domain
MH  - Crystallography, X-Ray
MH  - Growth Substances/chemistry
MH  - Humans
MH  - Kinetics
MH  - Models, Molecular
MH  - Molecular Sequence Data
MH  - Multigene Family
MH  - Mutagenesis, Site-Directed
MH  - *Neovascularization, Physiologic
MH  - Peptide Fragments/chemistry
MH  - *Protein Conformation
MH  - Protein Folding
MH  - Protein Structure, Secondary
MH  - Protein-Tyrosine Kinases/chemistry
MH  - Receptor Protein-Tyrosine Kinases/*chemistry/genetics/physiology
MH  - Receptors, Growth Factor/*chemistry/genetics/physiology
MH  - Receptors, Vascular Endothelial Growth Factor
MH  - Recombinant Fusion Proteins/chemistry
MH  - Sequence Alignment
MH  - Sequence Homology, Amino Acid
MH  - Structure-Activity Relationship
MH  - Substrate Specificity
EDAT- 1999/06/16 00:00
MHDA- 1999/06/16 00:01
CRDT- 1999/06/16 00:00
PHST- 1999/06/16 00:00 [pubmed]
PHST- 1999/06/16 00:01 [medline]
PHST- 1999/06/16 00:00 [entrez]
AID - S0969-2126(99)80042-2 [pii]
AID - 10.1016/s0969-2126(99)80042-2 [doi]
PST - ppublish
SO  - Structure. 1999 Mar 15;7(3):319-30. doi: 10.1016/s0969-2126(99)80042-2.