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| | ==Crystal structure of VEGF-A in complex with VEGFR-1 domains D1-6== | | ==Crystal structure of VEGF-A in complex with VEGFR-1 domains D1-6== |
| - | <StructureSection load='5t89' size='340' side='right' caption='[[5t89]], [[Resolution|resolution]] 4.00Å' scene=''> | + | <StructureSection load='5t89' size='340' side='right'caption='[[5t89]], [[Resolution|resolution]] 4.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5t89]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5T89 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5T89 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5t89]] 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=5T89 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5T89 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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]] 4Å</td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></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=5t89 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5t89 OCA], [http://pdbe.org/5t89 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5t89 RCSB], [http://www.ebi.ac.uk/pdbsum/5t89 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5t89 ProSAT]</span></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=5t89 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5t89 OCA], [https://pdbe.org/5t89 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5t89 RCSB], [https://www.ebi.ac.uk/pdbsum/5t89 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5t89 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/VEGFA_HUMAN VEGFA_HUMAN]] Defects in VEGFA are a cause of susceptibility to microvascular complications of diabetes type 1 (MVCD1) [MIM:[http://omim.org/entry/603933 603933]]. These are pathological conditions that develop in numerous tissues and organs as a consequence of diabetes mellitus. They include diabetic retinopathy, diabetic nephropathy leading to end-stage renal disease, and diabetic neuropathy. Diabetic retinopathy remains the major cause of new-onset blindness among diabetic adults. It is characterized by vascular permeability and increased tissue ischemia and angiogenesis. [[http://www.uniprot.org/uniprot/VGFR1_HUMAN VGFR1_HUMAN]] Note=Can contribute to cancer cell survival, proliferation, migration, and invasion, and tumor angiogenesis and metastasis. May contribute to cancer pathogenesis by promoting inflammatory responses and recruitment of tumor-infiltrating macrophages. Note=Abnormally high expression of soluble isoforms (isoform 2, isoform 3 or isoform 4) may be a cause of preeclampsia. | + | [https://www.uniprot.org/uniprot/VEGFA_HUMAN VEGFA_HUMAN] Defects in VEGFA are a cause of susceptibility to microvascular complications of diabetes type 1 (MVCD1) [MIM:[https://omim.org/entry/603933 603933]. These are pathological conditions that develop in numerous tissues and organs as a consequence of diabetes mellitus. They include diabetic retinopathy, diabetic nephropathy leading to end-stage renal disease, and diabetic neuropathy. Diabetic retinopathy remains the major cause of new-onset blindness among diabetic adults. It is characterized by vascular permeability and increased tissue ischemia and angiogenesis. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/VEGFA_HUMAN VEGFA_HUMAN]] Growth factor active in angiogenesis, vasculogenesis and endothelial cell growth. Induces endothelial cell proliferation, promotes cell migration, inhibits apoptosis and induces permeabilization of blood vessels. Binds to the FLT1/VEGFR1 and KDR/VEGFR2 receptors, heparan sulfate and heparin. NRP1/Neuropilin-1 binds isoforms VEGF-165 and VEGF-145. Isoform VEGF165B binds to KDR but does not activate downstream signaling pathways, does not activate angiogenesis and inhibits tumor growth.<ref>PMID:11427521</ref> <ref>PMID:15520188</ref> <ref>PMID:16489009</ref> [[http://www.uniprot.org/uniprot/VGFR1_HUMAN VGFR1_HUMAN]] Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFB and PGF, and plays an essential role in the development of embryonic vasculature, the regulation of angiogenesis, cell survival, cell migration, macrophage function, chemotaxis, and cancer cell invasion. May play an essential role as a negative regulator of embryonic angiogenesis by inhibiting excessive proliferation of endothelial cells. Can promote endothelial cell proliferation, survival and angiogenesis in adulthood. Its function in promoting cell proliferation seems to be cell-type specific. Promotes PGF-mediated proliferation of endothelial cells, proliferation of some types of cancer cells, but does not promote proliferation of normal fibroblasts (in vitro). Has very high affinity for VEGFA and relatively low protein kinase activity; may function as a negative regulator of VEGFA signaling by limiting the amount of free VEGFA and preventing its binding to KDR. Likewise, isoforms lacking a transmembrane domain, such as isoform 2, isoform 3 and isoform 4, may function as decoy receptors for VEGFA. Modulates KDR signaling by forming heterodimers with KDR. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leading to activation of phosphatidylinositol kinase and the downstream signaling pathway. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Phosphorylates SRC and YES1, and may also phosphorylate CBL. Isoform 1 phosphorylates PLCG. Promotes phosphorylation of AKT1 at 'Ser-473'. Promotes phosphorylation of PTK2/FAK1. Isoform 7 has a truncated kinase domain; it increases phosphorylation of SRC at 'Tyr-418' by unknown means and promotes tumor cell invasion.<ref>PMID:8248162</ref> <ref>PMID:18593464</ref> <ref>PMID:18515749</ref> <ref>PMID:20512933</ref> <ref>PMID:7824266</ref> <ref>PMID:8605350</ref> <ref>PMID:9299537</ref> <ref>PMID:11141500</ref> <ref>PMID:11811792</ref> <ref>PMID:11312102</ref> <ref>PMID:14633857</ref> <ref>PMID:12796773</ref> <ref>PMID:15735759</ref> <ref>PMID:16685275</ref> <ref>PMID:18079407</ref> <ref>PMID:18583712</ref> <ref>PMID:20551949</ref> <ref>PMID:21752276</ref> | + | [https://www.uniprot.org/uniprot/VEGFA_HUMAN VEGFA_HUMAN] Growth factor active in angiogenesis, vasculogenesis and endothelial cell growth. Induces endothelial cell proliferation, promotes cell migration, inhibits apoptosis and induces permeabilization of blood vessels. Binds to the FLT1/VEGFR1 and KDR/VEGFR2 receptors, heparan sulfate and heparin. NRP1/Neuropilin-1 binds isoforms VEGF-165 and VEGF-145. Isoform VEGF165B binds to KDR but does not activate downstream signaling pathways, does not activate angiogenesis and inhibits tumor growth.<ref>PMID:11427521</ref> <ref>PMID:15520188</ref> <ref>PMID:16489009</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5t89" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5t89" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[VEGF 3D Structures|VEGF 3D Structures]] |
| | + | *[[3D structures of vascular endothelial growth factor receptor|3D structures of vascular endothelial growth factor receptor]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Receptor protein-tyrosine kinase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Asthana, M]] | + | [[Category: Large Structures]] |
| - | [[Category: Ballmer-Hofer, K]] | + | [[Category: Asthana M]] |
| - | [[Category: Bliven, S]] | + | [[Category: Ballmer-Hofer K]] |
| - | [[Category: Capitani, G]] | + | [[Category: Bliven S]] |
| - | [[Category: Goldie, K N]] | + | [[Category: Capitani G]] |
| - | [[Category: Kisko, K]] | + | [[Category: Goldie KN]] |
| - | [[Category: Markovic-Mueller, S]] | + | [[Category: Kisko K]] |
| - | [[Category: Stuttfeld, E]] | + | [[Category: Markovic-Mueller S]] |
| - | [[Category: Weinert, T]] | + | [[Category: Stuttfeld E]] |
| - | [[Category: Growth factor]]
| + | [[Category: Weinert T]] |
| - | [[Category: Immunoglobulin domain]]
| + | |
| - | [[Category: Receptor tyrosine kinase]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Disease
VEGFA_HUMAN Defects in VEGFA are a cause of susceptibility to microvascular complications of diabetes type 1 (MVCD1) [MIM:603933. These are pathological conditions that develop in numerous tissues and organs as a consequence of diabetes mellitus. They include diabetic retinopathy, diabetic nephropathy leading to end-stage renal disease, and diabetic neuropathy. Diabetic retinopathy remains the major cause of new-onset blindness among diabetic adults. It is characterized by vascular permeability and increased tissue ischemia and angiogenesis.
Function
VEGFA_HUMAN Growth factor active in angiogenesis, vasculogenesis and endothelial cell growth. Induces endothelial cell proliferation, promotes cell migration, inhibits apoptosis and induces permeabilization of blood vessels. Binds to the FLT1/VEGFR1 and KDR/VEGFR2 receptors, heparan sulfate and heparin. NRP1/Neuropilin-1 binds isoforms VEGF-165 and VEGF-145. Isoform VEGF165B binds to KDR but does not activate downstream signaling pathways, does not activate angiogenesis and inhibits tumor growth.[1] [2] [3]
Publication Abstract from PubMed
Vascular endothelial growth factors (VEGFs) regulate blood and lymph vessel development upon activation of three receptor tyrosine kinases: VEGFR-1, -2, and -3. Partial structures of VEGFR/VEGF complexes based on single-particle electron microscopy, small-angle X-ray scattering, and X-ray crystallography revealed the location of VEGF binding and domain arrangement of individual receptor subdomains. Here, we describe the structure of the full-length VEGFR-1 extracellular domain in complex with VEGF-A at 4 A resolution. We combined X-ray crystallography, single-particle electron microscopy, and molecular modeling for structure determination and validation. The structure reveals the molecular details of ligand-induced receptor dimerization, in particular of homotypic receptor interactions in immunoglobulin homology domains 4, 5, and 7. Functional analyses of ligand binding and receptor activation confirm the relevance of these homotypic contacts and identify them as potential therapeutic sites to allosterically inhibit VEGFR-1 activity.
Structure of the Full-length VEGFR-1 Extracellular Domain in Complex with VEGF-A.,Markovic-Mueller S, Stuttfeld E, Asthana M, Weinert T, Bliven S, Goldie KN, Kisko K, Capitani G, Ballmer-Hofer K Structure. 2017 Jan 19. pii: S0969-2126(16)30402-6. doi:, 10.1016/j.str.2016.12.012. PMID:28111021[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Murphy JF, Fitzgerald DJ. Vascular endothelial growth factor induces cyclooxygenase-dependent proliferation of endothelial cells via the VEGF-2 receptor. FASEB J. 2001 Jul;15(9):1667-9. PMID:11427521
- ↑ Woolard J, Wang WY, Bevan HS, Qiu Y, Morbidelli L, Pritchard-Jones RO, Cui TG, Sugiono M, Waine E, Perrin R, Foster R, Digby-Bell J, Shields JD, Whittles CE, Mushens RE, Gillatt DA, Ziche M, Harper SJ, Bates DO. VEGF165b, an inhibitory vascular endothelial growth factor splice variant: mechanism of action, in vivo effect on angiogenesis and endogenous protein expression. Cancer Res. 2004 Nov 1;64(21):7822-35. PMID:15520188 doi:10.1158/0008-5472.CAN-04-0934
- ↑ Dixelius J, Olsson AK, Thulin A, Lee C, Johansson I, Claesson-Welsh L. Minimal active domain and mechanism of action of the angiogenesis inhibitor histidine-rich glycoprotein. Cancer Res. 2006 Feb 15;66(4):2089-97. PMID:16489009 doi:10.1158/0008-5472.CAN-05-2217
- ↑ Markovic-Mueller S, Stuttfeld E, Asthana M, Weinert T, Bliven S, Goldie KN, Kisko K, Capitani G, Ballmer-Hofer K. Structure of the Full-length VEGFR-1 Extracellular Domain in Complex with VEGF-A. Structure. 2017 Jan 19. pii: S0969-2126(16)30402-6. doi:, 10.1016/j.str.2016.12.012. PMID:28111021 doi:http://dx.doi.org/10.1016/j.str.2016.12.012
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