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A peptoid antagonist of VEGF receptor 2 recognizes a 'hotspot' in the extracellular domain distinct from the hormone-binding site

Academic Article
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Overview

authors

  • Udugamasooriya, D. G.
  • Ritchie, C.
  • Brekken, R. A.
  • Kodadek, Thomas

publication date

  • 2008

journal

  • Bioorganic & Medicinal Chemistry  Journal

abstract

  • 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.

subject areas

  • Angiogenesis Inhibitors
  • Animals
  • Binding Sites
  • Binding, Competitive
  • Cell Line
  • Humans
  • Ligands
  • Peptoids
  • Protein Structure, Tertiary
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor Receptor-2
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Research

keywords

  • VEGF receptor
  • peptoid
  • protein-ligand binding
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Identity

PubMed Central ID

  • PMC2460570

International Standard Serial Number (ISSN)

  • 0968-0896

Digital Object Identifier (DOI)

  • 10.1016/j.bmc.2008.05.015

PubMed ID

  • 18501615
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Additional Document Info

start page

  • 6338

end page

  • 6343

volume

  • 16

issue

  • 12

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