3I97

B1 domain of human Neuropilin-1 bound with small molecule EG00229

Summary for 3I97

• Entry DOI: 10.2210/pdb3i97/pdb
• Descriptor: Neuropilin-1, (S)-2-(3-(benzo[c][1,2,5]thiadiazole-4-sulfonamido)thiophene-2-carboxamido)-5-guanidinopentanoic acid, GLYCEROL, ... (4 entities in total)
• Functional Keywords: neuropilin-1, drug, vegf, angiogenesis, neuropilin, alternative splicing, cell membrane, developmental protein, differentiation, disulfide bond, glycoprotein, heparan sulfate, membrane, neurogenesis, phosphoprotein, polymorphism, proteoglycan, receptor, secreted, transmembrane, membrane protein, signaling protein
• Biological source: Homo sapiens (human)
• Cellular location: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted: O14786
• Total number of polymer chains: 2
• Total formula weight: 36921.82

Authors

Allerston, C.K.,Djordjevic, S. (deposition date: 2009-07-10, release date: 2010-03-02, Last modification date: 2024-11-20)

Primary citation

Jarvis, A.,Allerston, C.K.,Jia, H.,Herzog, B.,Garza-Garcia, A.,Winfield, N.,Ellard, K.,Aqil, R.,Lynch, R.,Chapman, C.,Hartzoulakis, B.,Nally, J.,Stewart, M.,Cheng, L.,Menon, M.,Tickner, M.,Djordjevic, S.,Driscoll, P.C.,Zachary, I.,Selwood, D.L.
Small molecule inhibitors of the neuropilin-1 vascular endothelial growth factor A (VEGF-A) interaction.
J.Med.Chem., 53:2215-2226, 2010

PubMed Abstract: We report the molecular design and synthesis of EG00229, 2, the first small molecule ligand for the VEGF-A receptor neuropilin 1 (NRP1) and the structural characterization of NRP1-ligand complexes by NMR spectroscopy and X-ray crystallography. Mutagenesis studies localized VEGF-A binding in the NRP1 b1 domain and a peptide fragment of VEGF-A was shown to bind at the same site by NMR, providing the basis for small molecule design. Compound 2 demonstrated inhibition of VEGF-A binding to NRP1 and attenuated VEGFR2 phosphorylation in endothelial cells. Inhibition of migration of endothelial cells was also observed. The viability of A549 lung carcinoma cells was reduced by 2, and it increased the potency of the cytotoxic agents paclitaxel and 5-fluorouracil when given in combination. These studies provide the basis for design of specific small molecule inhibitors of ligand binding to NRP1.

PubMed: 20151671
DOI: 10.1021/jm901755g

Experimental method

X-RAY DIFFRACTION (2.9 Å)