A peptoid antagonist of VEGF receptor 2 recognizes a 'hotspot' in the extracellular domain distinct from the hormone-binding site.
Antagonists of VEGF-mediated angiogenesis are of great interest clinically for the treatment of solid tumors and certain forms of macular degeneration. We recently described a novel peptoid antagonist of VEGF Receptor 2 (VEGFR2) that binds to the extracellular domain of the receptor and inhibits VEGF-mediated autophosphorylation and subsequent downstream signaling. Given the structural similarities between peptides and peptoids, an obvious model for the mode of action of the peptoid is that it competes with VEGF for binding to VEGFR2. However, we present evidence here that this is not the case and that VEGF and the peptoid antagonist recognize non-overlapping surfaces located within the first three immunoglobulin-like subdomains of the receptor. These data argue that the peptoid inhibits receptor-mediated autophosphorylation by a novel allosteric mechanism that may prevent the receptor from acquiring the conformation necessary to propagate downstream signals.
Udugamasooriya
D Gomika
DG
Department of Internal Medicine, Division of Translational Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-9185, USA.
Ritchie
Caroline
C
Brekken
Rolf A
RA
Kodadek
Thomas
T
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002460:Cell Line; D006801:Humans; D008024:Ligands; D034444:Peptoids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000737:chemistry
D020533:Angiogenesis Inhibitors; D008024:Ligands; D034444:Peptoids; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2