Structural Basis for Selective Vascular Endothelial Growth Factor-A (VEGF-A) Binding to Neuropilin-1

Parker, Matthew W.; Xu, Ping; Li, Xiaobo; Kooi, Craig W. Vander

doi:10.1074/jbc.m111.331140

Cited by 172 publications

(221 citation statements)

References 37 publications

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“…In 2012, Parker et al reported a crystal structure of mouse VEGF-A164a exons 7+8a-encoded sequence bound to NRP1. 18 The intermolecular interface, and experimental mutagenesis in the exon 8a-encoded sequence and NRP1 b1 domain residues, showed that exon 8a-encoded amino acids are critical for high affinity binding of any VEGF-A isoform to NRP1. 18 All NRP1-binding proteins and peptides are found to possess a C-terminal arginine.…”

Section: Evidence That the Exon 8a Domain Which Vegf-a121a Has Is Rmentioning

confidence: 99%

“…18 The intermolecular interface, and experimental mutagenesis in the exon 8a-encoded sequence and NRP1 b1 domain residues, showed that exon 8a-encoded amino acids are critical for high affinity binding of any VEGF-A isoform to NRP1. 18 All NRP1-binding proteins and peptides are found to possess a C-terminal arginine. 17 , 19 - 21 The authors further showed that NRP1 has a C-terminal arginine-binding pocket in the b1 domain.…”

Section: Evidence That the Exon 8a Domain Which Vegf-a121a Has Is Rmentioning

confidence: 99%

“…Mutating VEGF's C-terminal exon 8a-encoded arginine (R164) resulted in up to 97% loss in retention of mouse VEGF-A164a by NRP1, thus this residue plays a critical role in VEGF-A/NRP1 interactions (Fig. 3 of 18 ). Additional support for the key role of this arginine comes from a different VEGF ligand encoded by a different gene, VEGF-C, which can bind NRP2.…”

Section: Evidence That the Exon 8a Domain Which Vegf-a121a Has Is Rmentioning

confidence: 99%

“…HS chains on endothelial HSPGs stabilize this complex by binding to NRP1, VEGFR2 domain 6–7 and VEGF-A165a. (F) Binding (at lower affinity 18 , 27 ) of VEGF-A121a to NRP1 and VEGFR2 may form a weak extracellular bridge that can not be captured by immunoprecipitaion and cross-linking or (G) VEGF-A121a may alternatively only bind to VEGFR2 and activate the receptor dimer, (H) VEGF-A121a may predominantly bind to abundant NRP1 species on endothelial cell surface to activate the VEGFR2 receptor dimer. Upon binding to the receptors, VEGF-A121a and VEGF-A165a each may induce a conformationally distinct VEGFR/NRP/VEGF signaling complex (comparing E with F, G and H).…”

Section: Evidence That the Exon 8a Domain Which Vegf-a121a Has Is Rmentioning

confidence: 99%

“…Binding affinities of mouse VEGF-A120a and 164a to NRP1 (Fig. 2 of 18 ) were measured to be 3 nM and 22 nM respectively. VEGF-A120a, which lacks exons 6 and 7 (the ‘heparin-binding domain’ 22 ), binds with higher affinity to NRP2 than to NRP1; mouse VEGF-A164a, which has exon 7, binds to NRP1 with higher affinity than to NRP2 (Fig.…”

Section: Evidence That the Exon 8a Domain Which Vegf-a121a Has Is Rmentioning

confidence: 99%

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VEGF-A121a binding to Neuropilins – A concept revisited

Sarabipour

Gabhann

2017

Cell Adhesion & Migration

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All known splice isoforms of vascular endothelial growth factor A (VEGF-A) can bind to the receptor tyrosine kinases VEGFR-1 and VEGFR-2. We focus here on VEGF-A121a and VEGF-A165a, two of the most abundant VEGF-A splice isoforms in human tissue1, and their ability to bind the Neuropilin co-receptors NRP1 and NRP2. The Neuropilins are key vascular, immune, and nervous system receptors on endothelial cells, neuronal axons, and regulatory T cells respectively. They serve as co-receptors for the Plexins in Semaphorin binding on neuronal and vascular endothelial cells, and for the VEGFRs in VEGF binding on vascular and lymphatic endothelial cells, and thus regulate the initiation and coordination of cell signaling by Semaphorins and VEGFs.2 There is conflicting evidence in the literature as to whether only heparin-binding VEGF-A isoforms – that is, isoforms with domains encoded by exons 6 and/or 7 plus 8a – bind to Neuropilins on endothelial cells. While it is clear that VEGF-A165a binds to both NRP1 and NRP2, published studies do not all agree on the ability of VEGF-A121a to bind NRPs. Here, we review and attempt to reconcile evidence for and against VEGF-A121a binding to Neuropilins. This evidence suggests that, in vitro, VEGF-A121a can bind to both NRP1 and NRP2 via domains encoded by exons 5 and 8a; in the case of NRP1, VEGF-A121a binds with lower affinity than VEGF-A165a. In in vitro cell culture experiments, both NRP1 and NRP2 can enhance VEGF-A121a-induced phosphorylation of VEGFR2 and downstream signaling including proliferation. However, unlike VEGFA-165a, experiments have shown that VEGF-A121a does not ‘bridge’ VEGFR2 and NRP1, i.e. it does not bind both receptors simultaneously at their extracellular domain. Thus, the mechanism by which Neuropilins potentiate VEGF-A121a-mediated VEGFR2 signaling may be different from that for VEGF-A165a. We suggest such an alternate mechanism: interactions between NRP1 and VEGFR2 transmembrane (TM) and intracellular (IC) domains.

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Section: Evidence That the Exon 8a Domain Which Vegf-a121a Has Is Rmentioning

confidence: 99%

Section: Evidence That the Exon 8a Domain Which Vegf-a121a Has Is Rmentioning

confidence: 99%

Section: Evidence That the Exon 8a Domain Which Vegf-a121a Has Is Rmentioning

confidence: 99%

Section: Evidence That the Exon 8a Domain Which Vegf-a121a Has Is Rmentioning

confidence: 99%

Section: Evidence That the Exon 8a Domain Which Vegf-a121a Has Is Rmentioning

confidence: 99%

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VEGF-A121a binding to Neuropilins – A concept revisited

Sarabipour

Gabhann

2017

Cell Adhesion & Migration

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Identification of Four New Chemical Series of Small Drug‐Like Natural Products as Potential Neuropilin‐1 Inhibitors by Structure‐Based Virtual Screening: Pharmacophore‐Based Molecular Docking and Dynamics Simulation

Sabki

Khelifi

Kameli

et al. 2023

Chemistry & Biodiversity

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Neuropilin-1 (NRP-1), a surface transmembrane glycoprotein, is one of the most important co-receptors of VEGF-A165 (vascular endothelial growth factor) responsible for pathological angiogenesis. In general, NRP-1 overexpression in cancer correlates with poor prognosis and more tumor aggressiveness. NRP-1 role in cancer has been mainly explained by mediating VEGF-A165-induced effects on tumor angiogenesis. NRP-1 was recently identified as a co-receptor and an independent gateway for SARS-CoV-2 through binding subunit S2 of Spike protein in the same way as VEGF-A165. Thus, NRP-1 is of particular value as a target for cancer therapy and other angiogenesis-dependent diseases as well as for SARS-CoV-2 antiviral intervention. Herein, The Super Natural II, the largest available database of natural products (~0.33 M), pre-filtered with drug-likeness criteria (absorption, distribution, metabolism and excretion/toxicity), was screened against NRP-1. NRP-1/VEGF-A165 interaction is one of protein-protein interfaces (PPIs) known to be challenging when approached in-silico. Thus, a PPI-suited multi-step virtual screening protocol, incorporating a derived pharmacophore with molecular docking and followed by MD (molecular dynamics) simulation, was designed. Two stages of pharmacophorically constrained molecular docking (standard and extra precisions), a mixed Torsional/Low-mode conformational search and MM-GBSA ΔG binding affinities calculation, resulted in the selection of 100 hits. These 100 hits were subjected to 20 ns MD simulation, that was extended to 100 ns for top hits (20) and followed by post-dynamics analysis (atomic ligand-protein contacts, RMSD, RMSF, MM-GBSA ΔG, Rg, SASA and H-bonds). Post-MD analysis showed that 19 small drug-like nonpeptide natural molecules, grouped in four chemical scaffolds (purine, thiazole, tetrahydropyrimidine and dihydroxyphenyl), well verified the derived pharmacophore and formed stable and compact complexes with NRP-1. The discovered molecules are promising and can serve as a base for further development of new NRP-1 inhibitors.

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N‐Terminal Modification of VEGF‐A C Terminus‐Derived Peptides Delineates Structural Features Involved in Neuropilin‐1 Binding and Functional Activity

et al. 2014

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The interaction between VEGF-A and its neuropilin (NRP) receptors mediates a number of important biological effects. NRP1 and the related molecule NRP2 are widely expressed on multiple tumour types and throughout the tumour vasculature, and are emerging as critical molecules required for the progression of angiogenic diseases. Given the increasing evidence supporting a role for NRP1 in tumour development, there is growing interest in developing inhibitors of NRP1 interactions with VEGF and its other ligands. In order to probe the interaction we synthesised a number of exon 7- and 8-derived bicyclic peptides with N-terminal lipophilic groups and found a simple N-octanoyl derivative (EG00086) to be the most potent and functionally active. Detailed modelling studies indicated that new intramolecular hydrogen bonds were formed, stabilising the structure and possibly contributing to the potency. Removal of a salt bridge between D142 and R164 implicated in VEGF-A binding to neuropilin-1 had a minor effect on potency. Isothermal calorimetry was used to assess binding of EG00086 to NRP1 and NRP2, and the stability of the peptide in serum and in vivo was investigated. EG00086 is a potent blocker of VEGF-promoted cellular adhesion to extracellular matrices, and phosphorylation of p130Cas contributes to this effect.

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Structural Basis for Selective Vascular Endothelial Growth Factor-A (VEGF-A) Binding to Neuropilin-1

Cited by 172 publications

References 37 publications

VEGF-A121a binding to Neuropilins – A concept revisited

VEGF-A121a binding to Neuropilins – A concept revisited

Identification of Four New Chemical Series of Small Drug‐Like Natural Products as Potential Neuropilin‐1 Inhibitors by Structure‐Based Virtual Screening: Pharmacophore‐Based Molecular Docking and Dynamics Simulation

N‐Terminal Modification of VEGF‐A C Terminus‐Derived Peptides Delineates Structural Features Involved in Neuropilin‐1 Binding and Functional Activity

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