Structural basis for the interaction of a vascular endothelial growth factor mimic peptide motif and its corresponding receptors.
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.
Giordano
Ricardo J
RJ
The University of Texas, MD Anderson Cancer Center, Houston, 77030, USA.
Anobom
Cristiane D
CD
Cardó-Vila
Marina
M
Kalil
Jorge
J
Valente
Ana P
AP
Pasqualini
Renata
R
Almeida
Fabio C L
FC
Arap
Wadih
W
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*
D010456:Peptides, Cyclic; D042442:Vascular Endothelial Growth Factors; D039942:Neuropilin-1; D040281:Vascular Endothelial Growth Factor Receptor-1