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Kinase domain of human VEGFR1 (FLT1)

PDB Code 3HNG Target Class Protein Kinase Target FLT1 (KINASE DOMAIN) Alias n/a Disease Area/Function cancer Date Deposited May 31 2009 Authors Tresaugues, L., Roos, A., Arrowsmith, C.H., Berglund, H., Bountra, C., Collins, R., Edwards, A.M., Flodin, S., Flores, A., Graslund, S., Hammarstrom, M., Johansson, A., Johansson, I., Karlberg, T., Kotyenova, T., Kotzch, A., Moche, M., Nielsen, T.K., Nyman, T., Persson, C., Sagemark, J., Schueler, H., Schutz, P., Siponen, M.I., Svensson, L., Thorsell, A.G., Van Den Berg, S., Weigelt, J., Welin, M., Wisniewska, M., Nordlund, P. Structural Genomics Consortium (SGC)

About this structure

ascular endothelial growth factor receptor 1 (VEGFR-1, FLT-1) is a receptor tyrosine kinase (RTK) which belongs to a family of type III receptor tyrosine kinase. This family includes the colony-stimulating factor 1 receptor, FLT-3 receptor, FLT-4 (VEGFR-3), VEGFR-2, the platelet-derived growth factor α and β and c-Kit. The characteristics of this family are: i) an extracellular domain composed by multiple copies of immunoglobulin domains (7 for both FLT-1 and VEGFR-2), ii) a single transmembrane helix, iii) an autoinhibitory juxtamembrane domain and iv) a kinase insertion domain (KID) which disrupts the C-lobe of the catalytic kinase domain [1, 2]. VEGFR-1 can both promote or inhibit angiogenesis [3, 4] and is thus involved in angiogenesis related pathology as cancer or retinopathy of prematurity [5, 6]. Signalling through VEGFR-1 is linked to binding to three different ligands : PLGF, VEGF-A and VEGF-B. Actually the proposed model of VEGFR-1-mediated regulation could be initiated in three different way of action : i) VEGF-trapping by capturing VEGFR-2 ligand thus antagonizing VEGFR-2 signaling [7], ii) heterodimerization with VEGFR-2 [8] and iii) homodimerization [8].
We have solved and refined to 2.7Å the structure of the catalytical domain of unphosphorylated VEGFR-1 complexed with N-(4-Chlorophenyl)-2-[(pyridin-4-ylmethyl)amino]benzamide, an inhibitor with a scaffold based upon anthranilic acid [9] (PDB entry: 3HNG). The protein construct used for crystallization encompasses residues 801 to 1158 from human VEGFR-1 including 27 residues from the juxtamembrane domain and the full-length KID. Dataset was collected on ESRF beamline ID14-2 and structure was solved by molecular replacement using the structure of the catalytical domain of VEGFR2 in complex with a benzimidazole inhibitor (PDB entry : 2QU5) [10]. The model has been refined to lead to R and Rfree values of respectively 19.4% and 26%.
VEGFR-1 adopts the classic kinase fold with a N-lobe constituted mostly by β-sheets and a helical C-lobe. The structure shows VEGFR-1 in the inhibited state previously described for this family of protein [11] in where the activation loop is in a “closed conformation” between the N- and C- lobe. Thus, Tyr1053 is located in the active site playing the role of a pseudo- substrate. This unactive state is maintained by the inhibitor which restrained the DFG motif in a conformation very similar to one produced by juxtamembrane autoinhibiton. If 26 residues of the juxtamembrane domain are clearly visible in the density, position of only 7 out of 72 residues of the KID could be attributed due to the intrinsic disorder of this region.

References

  1. Yarden, Y., et al., Structure of the receptor for platelet-derived growth factor helps define a family of closely related growth factor receptors. Nature, 1986. 323(6085): p. 226-32.
  2. Ullrich, A. and J. Schlessinger, Signal transduction by receptors with tyrosine kinase activity. Cell, 1990. 61(2): p. 203-12.
  3. Fong, G.H., et al., Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature, 1995. 376(6535): p. 66-70.
  4. Fong, G.H., et al., Increased hemangioblast commitment, not vascular disorganization, is the primary defect in flt-1 knock-out mice. Development, 1999. 126(13): p. 3015-25.
  5. Shih, S.C., et al., Selective stimulation of VEGFR-1 prevents oxygen-induced retinal vascular degeneration in retinopathy of prematurity. J Clin Invest, 2003. 112(1): p. 50-7.
  6. Wey, J.S., et al., Vascular endothelial growth factor receptor-1 promotes migration and invasion in pancreatic carcinoma cell lines. Cancer, 2005. 104(2): p. 427-38.
  7. Hiratsuka, S., et al., Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc Natl Acad Sci U S A, 1998. 95(16): p. 9349-54.
  8. Rahimi, N., V. Dayanir, and K. Lashkari, Receptor chimeras indicate that the vascular endothelial growth factor receptor-1 (VEGFR-1) modulates mitogenic activity of VEGFR-2 in endothelial cells. J Biol Chem, 2000. 275(22): p. 16986-92.
  9. Furet, P., et al., Identification of a new chemical class of potent angiogenesis inhibitors based on conformational considerations and database searching. Bioorg Med Chem Lett, 2003. 13(18): p. 2967-71.
  10. Potashman, M.H., et al., Design, synthesis, and evaluation of orally active benzimidazoles and benzoxazoles as vascular endothelial growth factor-2 receptor tyrosine kinase inhibitors. J Med Chem, 2007. 50(18): p. 4351-73.
  11. Griffith, J., et al., The structural basis for autoinhibition of FLT3 by the juxtamembrane domain. Mol Cell, 2004. 13(2): p. 169-78.