title: Structural basis for the interaction of a vascular endothelial growth factor mimic peptide motif and its corresponding receptors.
abstract: Vascular endothelial growth factor (VEGF) is central to the survival and development of the vascular and nervous systems. We screened phage display libraries and built a peptide-based ligand-receptor map of binding sites within the VEGF family. We then validated a cyclic peptide, CPQPRPLC, as a VEGF-mimic that binds specifically to neuropilin-1 and VEGF receptor-1. Here, we use NMR spectroscopy to understand the structural basis of the interaction between our mimic peptide and the VEGF receptors. We show that: (1) CPQPRPLC has multiple interactive conformations; (2) receptor binding is mediated by the motif Arg-Pro-Leu; and (3) the Pro residue within Arg-Pro-Leu participates in binding to neuropilin-1 but not to VEGF receptor-1, perhaps representing an evolutionary gain-of-function. Therefore, Arg-Pro-Leu is a differential ligand motif to VEGF receptors and a candidate peptidomimetic lead for VEGF pathway modulation.
authors.affiliation: The University of Texas, MD Anderson Cancer Center, Houston, 77030, USA.
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Giordano
authors.forename: Cristiane D
authors.initials: CD
authors.lastname: Anobom
authors.forename: Marina
authors.initials: M
authors.lastname: Cardó-Vila
authors.forename: Jorge
authors.initials: J
authors.lastname: Kalil
authors.forename: Ana P
authors.initials: AP
authors.lastname: Valente
authors.forename: Renata
authors.initials: R
authors.lastname: Pasqualini
authors.forename: Fabio C L
authors.initials: FC
authors.lastname: Almeida
authors.forename: Wadih
authors.initials: W
authors.lastname: Arap
mesh_terms: D020816:Amino Acid Motifs; D001665:Binding Sites; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D039942:Neuropilin-1 / Q000378:metabolism; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D042442:Vascular Endothelial Growth Factors / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D010456:Peptides, Cyclic; D042442:Vascular Endothelial Growth Factors; D039942:Neuropilin-1; D040281:Vascular Endothelial Growth Factor Receptor-1