Target Information
| Target General Information | Top | |||||
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| Target ID |
T15023
(Former ID: TTDC00183)
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| Target Name |
Neuropilin-1 (NRP1)
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| Synonyms |
Vascular endothelial cell growth factor 165 receptor; VEGF165R; Platelet-derived endothelial cell growth factor receptor; NRP; Membrane-bound; CD304
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| Gene Name |
NRP1
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Retinopathy [ICD-11: 9B71] | |||||
| Function |
It mediates the chemorepulsant activity of semaphorins. It binds to semaphorin 3A, The PLGF-2 isoform of PGF, The VEGF165 isoform of VEGFA and VEGFB. Coexpression with KDR results in increased VEGF165 binding to KDR as well as increased chemotaxis. Regulate VEGF-induced angiogenesis. Binding to VEGFA initiates a signaling pathway needed for motor neuron axon guidance and cell body migration, including for the caudal migration of facial motor neurons from rhombomere 4 to rhombomere 6 during embryonic development. The membrane-bound isoform 1 is a receptor involved in the development of the cardiovascular system, in angiogenesis, in the formation of certain neuronal circuits and in organogenesis outside the nervous system.
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| BioChemical Class |
Neuropilin and tolloid-like
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| UniProt ID | ||||||
| Sequence |
MERGLPLLCAVLALVLAPAGAFRNDKCGDTIKIESPGYLTSPGYPHSYHPSEKCEWLIQA
PDPYQRIMINFNPHFDLEDRDCKYDYVEVFDGENENGHFRGKFCGKIAPPPVVSSGPFLF IKFVSDYETHGAGFSIRYEIFKRGPECSQNYTTPSGVIKSPGFPEKYPNSLECTYIVFVP KMSEIILEFESFDLEPDSNPPGGMFCRYDRLEIWDGFPDVGPHIGRYCGQKTPGRIRSSS GILSMVFYTDSAIAKEGFSANYSVLQSSVSEDFKCMEALGMESGEIHSDQITASSQYSTN WSAERSRLNYPENGWTPGEDSYREWIQVDLGLLRFVTAVGTQGAISKETKKKYYVKTYKI DVSSNGEDWITIKEGNKPVLFQGNTNPTDVVVAVFPKPLITRFVRIKPATWETGISMRFE VYGCKITDYPCSGMLGMVSGLISDSQITSSNQGDRNWMPENIRLVTSRSGWALPPAPHSY INEWLQIDLGEEKIVRGIIIQGGKHRENKVFMRKFKIGYSNNGSDWKMIMDDSKRKAKSF EGNNNYDTPELRTFPALSTRFIRIYPERATHGGLGLRMELLGCEVEAPTAGPTTPNGNLV DECDDDQANCHSGTGDDFQLTGGTTVLATEKPTVIDSTIQSEFPTYGFNCEFGWGSHKTF CHWEHDNHVQLKWSVLTSKTGPIQDHTGDGNFIYSQADENQKGKVARLVSPVVYSQNSAH CMTFWYHMSGSHVGTLRVKLRYQKPEEYDQLVWMAIGHQGDHWKEGRVLLHKSLKLYQVI FEGEIGKGNLGGIAVDDISINNHISQEDCAKPADLDKKNPEIKIDETGSTPGYEGEGEGD KNISRKPGNVLKTLDPILITIIAMSALGVLLGAVCGVVLYCACWHNGMSERNLSALENYN FELVDGVKLKKDKLNTQSTYSEA Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T36U0M | |||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
| 1 | Pegaptanib | Drug Info | Approved | Neovascular age-related macular degeneration | [2], [3], [4] | |
| Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
| 1 | ASP1948 | Drug Info | Phase 1 | Solid tumour/cancer | [5] | |
| 2 | RG7347 | Drug Info | Phase 1 | Solid tumour/cancer | [6] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 2 Inhibitor drugs | + | ||||
| 1 | ASP1948 | Drug Info | [8] | |||
| 2 | H-KPPR-OH | Drug Info | [9] | |||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | RG7347 | Drug Info | [1] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: L-Homoarginine | Ligand Info | |||||
| Structure Description | X-ray structure of neuropilin-1 b1 domain complexed with Arg-1 ligand. | PDB:5IJR | ||||
| Method | X-ray diffraction | Resolution | 1.52 Å | Mutation | No | [10] |
| PDB Sequence |
KCMEALGMES
283 GEIHSDQITA293 SSQYSTNWSA303 ERSRLNYPEN313 GWTPGEDSYR323 EWIQVDLGLL 333 RFVTAVGTQG343 AISKETKKKY353 YVKTYKIDVS363 SNGEDWITIK373 EGNKPVLFQG 383 NTNPTDVVVA393 VFPKPLITRF403 VRIKPATWET413 GISMRFEVYG423 CKIT |
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| Ligand Name: Tris(hydroxyethyl)aminomethane | Ligand Info | |||||
| Structure Description | MAM domain of human neuropilin-1 | PDB:5L73 | ||||
| Method | X-ray diffraction | Resolution | 2.24 Å | Mutation | No | [11] |
| PDB Sequence |
QDEFPDYGFN
649 CEFGWGSHKT659 FCHWEHDNHV669 QLKWSVLTSK679 TGPIQDHTGD689 GNFIYSQADE 699 NQKGKVARLV709 SPVVYSQNSA719 HCMTFWYHMS729 GSHVGTLRVK739 LRYQKPEEYD 749 QLVWMAIGHQ759 GDHWKEGRVL769 LHKSLKLYQV779 IFEGEIGKGN789 LGGIAVDDIS 799 INNHISQEDC809 AKPA
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Axon guidance | hsa04360 | Affiliated Target |
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| Class: Organismal Systems => Development and regeneration | Pathway Hierarchy | ||
| Degree | 22 | Degree centrality | 2.36E-03 | Betweenness centrality | 2.31E-03 |
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| Closeness centrality | 2.13E-01 | Radiality | 1.37E+01 | Clustering coefficient | 9.96E-02 |
| Neighborhood connectivity | 9.91E+00 | Topological coefficient | 8.07E-02 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target-regulating Transcription Factors | ||||||
| Target-interacting Proteins | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
| 1 | Axon guidance | |||||
| 2 | HTLV-I infection | |||||
| Panther Pathway | [+] 1 Panther Pathways | + | ||||
| 1 | Axon guidance mediated by semaphorins | |||||
| PID Pathway | [+] 3 PID Pathways | + | ||||
| 1 | VEGF and VEGFR signaling network | |||||
| 2 | Plexin-D1 Signaling | |||||
| 3 | VEGFR1 specific signals | |||||
| Reactome | [+] 3 Reactome Pathways | + | ||||
| 1 | Neurophilin interactions with VEGF and VEGFR | |||||
| 2 | CRMPs in Sema3A signaling | |||||
| 3 | CHL1 interactions | |||||
| WikiPathways | [+] 7 WikiPathways | + | ||||
| 1 | miR-targeted genes in squamous cell - TarBase | |||||
| 2 | miR-targeted genes in muscle cell - TarBase | |||||
| 3 | miR-targeted genes in lymphocytes - TarBase | |||||
| 4 | miR-targeted genes in epithelium - TarBase | |||||
| 5 | Signaling by VEGF | |||||
| 6 | Semaphorin interactions | |||||
| 7 | L1CAM interactions | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Neuropilin-1 as Therapeutic Target for Malignant Melanoma. Front Oncol. 2015; 5: 125. | |||||
| REF 2 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6836). | |||||
| REF 3 | Future pharmacological treatment options for nonexudative and exudative age-related macular degeneration. Expert Opin Emerg Drugs. 2005 Feb;10(1):119-35. | |||||
| REF 4 | Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease. Nat Rev Drug Discov. 2006 Feb;5(2):123-32. | |||||
| REF 5 | ClinicalTrials.gov (NCT04094506) Study of ASP1948, Targeting an Immune Modulatory Receptor, in Japanese Patients With Advanced Solid Tumors. U.S. National Institutes of Health. | |||||
| REF 6 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800027393) | |||||
| REF 7 | Pegaptanib in the treatment of wet, age-related macular degeneration. Int J Nanomedicine. 2006;1(3):263-8. | |||||
| REF 8 | National Cancer Institute Drug Dictionary (drug name ASP1948). | |||||
| REF 9 | Small molecule inhibitors of the neuropilin-1 vascular endothelial growth factor A (VEGF-A) interaction. J Med Chem. 2010 Mar 11;53(5):2215-26. | |||||
| REF 10 | Architecture and hydration of the arginine-binding site of neuropilin-1. FEBS J. 2018 Apr;285(7):1290-1304. | |||||
| REF 11 | Crystal Structure of the Neuropilin-1 MAM Domain: Completing the Neuropilin-1 Ectodomain Picture. Structure. 2016 Nov 1;24(11):2008-2015. | |||||
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