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| | ==X-ray structure of neuropilin-1 b1 domain complexed with Arg-5 ligand.== | | ==X-ray structure of neuropilin-1 b1 domain complexed with Arg-5 ligand.== |
| - | <StructureSection load='5j1x' size='340' side='right' caption='[[5j1x]], [[Resolution|resolution]] 2.10Å' scene=''> | + | <StructureSection load='5j1x' size='340' side='right'caption='[[5j1x]], [[Resolution|resolution]] 2.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5j1x]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5J1X OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5J1X FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5j1x]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5J1X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5J1X FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AR5:N~2~-(TERT-BUTOXYCARBONYL)-L-ARGININE'>AR5</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5ijr|5ijr]], [[1kex|1kex]], [[3i97|3i97]], [[5iyy|5iyy]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AR5:N~2~-(TERT-BUTOXYCARBONYL)-L-ARGININE'>AR5</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NRP1, NRP, VEGF165R ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5j1x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j1x OCA], [https://pdbe.org/5j1x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5j1x RCSB], [https://www.ebi.ac.uk/pdbsum/5j1x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5j1x ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5j1x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j1x OCA], [http://pdbe.org/5j1x PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5j1x RCSB], [http://www.ebi.ac.uk/pdbsum/5j1x PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5j1x ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/NRP1_HUMAN NRP1_HUMAN]] 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. It mediates the chemorepulsant activity of semaphorins. It binds to semaphorin 3A, The PLGF-2 isoform of PGF, The VEGF-165 isoform of VEGF and VEGF-B. Coexpression with KDR results in increased VEGF-165 binding to KDR as well as increased chemotaxis. It may regulate VEGF-induced angiogenesis. The soluble isoform 2 binds VEGF-165 and appears to inhibit its binding to cells. It may also induce apoptosis by sequestering VEGF-165. May bind as well various members of the semaphorin family. Its expression has an averse effect on blood vessel number and integrity. | + | [https://www.uniprot.org/uniprot/NRP1_HUMAN NRP1_HUMAN] 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. It mediates the chemorepulsant activity of semaphorins. It binds to semaphorin 3A, The PLGF-2 isoform of PGF, The VEGF-165 isoform of VEGF and VEGF-B. Coexpression with KDR results in increased VEGF-165 binding to KDR as well as increased chemotaxis. It may regulate VEGF-induced angiogenesis. The soluble isoform 2 binds VEGF-165 and appears to inhibit its binding to cells. It may also induce apoptosis by sequestering VEGF-165. May bind as well various members of the semaphorin family. Its expression has an averse effect on blood vessel number and integrity. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Djordjevic, S]] | + | [[Category: Large Structures]] |
| - | [[Category: Fotinou, C]] | + | [[Category: Djordjevic S]] |
| - | [[Category: Rana, R]] | + | [[Category: Fotinou C]] |
| - | [[Category: Yelland, T]] | + | [[Category: Rana R]] |
| - | [[Category: Angiogenesis]]
| + | [[Category: Yelland T]] |
| - | [[Category: Neuropilin-1]]
| + | |
| - | [[Category: Signaling protein]]
| + | |
| Structural highlights
Function
NRP1_HUMAN 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. It mediates the chemorepulsant activity of semaphorins. It binds to semaphorin 3A, The PLGF-2 isoform of PGF, The VEGF-165 isoform of VEGF and VEGF-B. Coexpression with KDR results in increased VEGF-165 binding to KDR as well as increased chemotaxis. It may regulate VEGF-induced angiogenesis. The soluble isoform 2 binds VEGF-165 and appears to inhibit its binding to cells. It may also induce apoptosis by sequestering VEGF-165. May bind as well various members of the semaphorin family. Its expression has an averse effect on blood vessel number and integrity.
Publication Abstract from PubMed
Neuropilin-1 (NRP1) is a transmembrane co-receptor involved in binding interactions with variety of ligands and receptors, including receptor tyrosine kinases. Expression of NRP1 in several cancers correlates with cancer stages and poor prognosis. Thus, NRP1 has been considered a therapeutic target and is the focus of multiple drug discovery initiatives. Vascular endothelial growth factor (VEGF) binds to the b1 domain of NRP1 through interactions between the C-terminal arginine of VEGF and residues in the NRP1-binding site including Tyr297, Tyr353, Asp320, Ser346 and Thr349. We obtained several complexes of the synthetic ligands and the NRP1-b1 domain and used X-ray crystallography and computational methods to analyse atomic details and hydration profile of this binding site. We observed side chain flexibility for Tyr297 and Asp320 in the six new high-resolution crystal structures of arginine analogues bound to NRP1. In addition, we identified conserved water molecules in binding site regions which can be targeted for drug design. The computational prediction of the VEGF ligand-binding site hydration map of NRP1 was in agreement with the experimentally derived, conserved hydration structure. Displacement of certain conserved water molecules by a ligand's functional groups may contribute to binding affinity, whilst other water molecules perform as protein-ligand bridges. Our report provides a comprehensive description of the binding site for the peptidic ligands' C-terminal arginines in the b1 domain of NRP1, highlights the importance of conserved structural waters in drug design and validates the utility of the computational hydration map prediction method in the context of neuropilin. DATABASE: The structures were deposited to the PDB with accession numbers PDB ID: 5IJR, 5IYY, 5JHK, 5J1X, 5JGQ, 5JGI.
Architecture and hydration of the arginine-binding site of neuropilin-1.,Mota F, Fotinou C, Rhana R, Chan AWE, Yelland T, Arooz MT, O'Leary AP, Hutton J, Frankel P, Zachary I, Selwood D, Djordjevic S FEBS J. 2018 Feb 12. doi: 10.1111/febs.14405. PMID:29430837[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Mota F, Fotinou C, Rhana R, Chan AWE, Yelland T, Arooz MT, O'Leary AP, Hutton J, Frankel P, Zachary I, Selwood D, Djordjevic S. Architecture and hydration of the arginine-binding site of neuropilin-1. FEBS J. 2018 Feb 12. doi: 10.1111/febs.14405. PMID:29430837 doi:http://dx.doi.org/10.1111/febs.14405
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