4bsj - Revision history

OCA at 17:04, 7 September 2022

OCA — Wed, 07 Sep 2022 17:04:48 GMT

←Older revision		Revision as of 17:04, 7 September 2022
Line 3:		Line 3:
	<StructureSection load='4bsj' size='340' side='right'caption='[[4bsj]], [[Resolution\|resolution]] 2.50Å' scene=''>		<StructureSection load='4bsj' size='340' side='right'caption='[[4bsj]], [[Resolution\|resolution]] 2.50Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4bsj]] is a 1 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=4BSJ OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4BSJ FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4bsj]] is a 1 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=4BSJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BSJ 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='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='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4bsk\|4bsk]]</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=4bsj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bsj OCA], [https://pdbe.org/4bsj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bsj RCSB], [https://www.ebi.ac.uk/pdbsum/4bsj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bsj ProSAT]</span></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='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=4bsj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bsj OCA], [~~http~~://pdbe.org/4bsj PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4bsj RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4bsj PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4bsj ProSAT]</span></td></tr>	+
	</table>		</table>
	== Disease ==		== Disease ==
-	[[~~http~~://www.uniprot.org/uniprot/VGFR3_HUMAN VGFR3_HUMAN]] Milroy disease. The disease is caused by mutations affecting the gene represented in this entry. Disease susceptibility is associated with variations affecting the gene represented in this entry. Plays an important role in tumor lymphangiogenesis, in cancer cell survival, migration, and formation of metastases.	+	[[https://www.uniprot.org/uniprot/VGFR3_HUMAN VGFR3_HUMAN]] Milroy disease. The disease is caused by mutations affecting the gene represented in this entry. Disease susceptibility is associated with variations affecting the gene represented in this entry. Plays an important role in tumor lymphangiogenesis, in cancer cell survival, migration, and formation of metastases.
	== Function ==		== Function ==
-	[[~~http~~://www.uniprot.org/uniprot/VGFR3_HUMAN VGFR3_HUMAN]] Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFC and VEGFD, and plays an essential role in adult lymphangiogenesis and in the development of the vascular network and the cardiovascular system during embryonic development. Promotes proliferation, survival and migration of endothelial cells, and regulates angiogenic sprouting. Signaling by activated FLT4 leads to enhanced production of VEGFC, and to a lesser degree VEGFA, thereby creating a positive feedback loop that enhances FLT4 signaling. Modulates KDR signaling by forming heterodimers. The secreted isoform 3 may function as a decoy receptor for VEGFC and/or VEGFD and play an important role as a negative regulator of VEGFC-mediated lymphangiogenesis and angiogenesis. Binding of vascular growth factors to isoform 1 or isoform 2 leads to the activation of several signaling cascades; isoform 2 seems to be less efficient in signal transduction, because it has a truncated C-terminus and therefore lacks several phosphorylation sites. Mediates activation of the MAPK1/ERK2, MAPK3/ERK1 signaling pathway, of MAPK8 and the JUN signaling pathway, and of the AKT1 signaling pathway. Phosphorylates SHC1. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Promotes phosphorylation of MAPK8 at 'Thr-183' and 'Tyr-185', and of AKT1 at 'Ser-473'.<ref>PMID:8700872</ref> <ref>PMID:7675451</ref> <ref>PMID:9435229</ref> <ref>PMID:11532940</ref> <ref>PMID:15474514</ref> <ref>PMID:15102829</ref> <ref>PMID:16076871</ref> <ref>PMID:16452200</ref> <ref>PMID:17210781</ref> <ref>PMID:19779139</ref> <ref>PMID:19610651</ref> <ref>PMID:20431062</ref> <ref>PMID:20224550</ref> <ref>PMID:20445537</ref> <ref>PMID:21273538</ref>	+	[[https://www.uniprot.org/uniprot/VGFR3_HUMAN VGFR3_HUMAN]] Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFC and VEGFD, and plays an essential role in adult lymphangiogenesis and in the development of the vascular network and the cardiovascular system during embryonic development. Promotes proliferation, survival and migration of endothelial cells, and regulates angiogenic sprouting. Signaling by activated FLT4 leads to enhanced production of VEGFC, and to a lesser degree VEGFA, thereby creating a positive feedback loop that enhances FLT4 signaling. Modulates KDR signaling by forming heterodimers. The secreted isoform 3 may function as a decoy receptor for VEGFC and/or VEGFD and play an important role as a negative regulator of VEGFC-mediated lymphangiogenesis and angiogenesis. Binding of vascular growth factors to isoform 1 or isoform 2 leads to the activation of several signaling cascades; isoform 2 seems to be less efficient in signal transduction, because it has a truncated C-terminus and therefore lacks several phosphorylation sites. Mediates activation of the MAPK1/ERK2, MAPK3/ERK1 signaling pathway, of MAPK8 and the JUN signaling pathway, and of the AKT1 signaling pathway. Phosphorylates SHC1. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Promotes phosphorylation of MAPK8 at 'Thr-183' and 'Tyr-185', and of AKT1 at 'Ser-473'.<ref>PMID:8700872</ref> <ref>PMID:7675451</ref> <ref>PMID:9435229</ref> <ref>PMID:11532940</ref> <ref>PMID:15474514</ref> <ref>PMID:15102829</ref> <ref>PMID:16076871</ref> <ref>PMID:16452200</ref> <ref>PMID:17210781</ref> <ref>PMID:19779139</ref> <ref>PMID:19610651</ref> <ref>PMID:20431062</ref> <ref>PMID:20224550</ref> <ref>PMID:20445537</ref> <ref>PMID:21273538</ref>
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are key drivers of blood and lymph vessel formation in development, but also in several pathological processes. VEGF-C signaling through VEGFR-3 promotes lymphangiogenesis, which is a clinically relevant target for treating lymphatic insufficiency and for blocking tumor angiogenesis and metastasis. The extracellular domain of VEGFRs consists of seven Ig homology domains; domains 1-3 (D1-3) are responsible for ligand binding, and the membrane-proximal domains 4-7 (D4-7) are involved in structural rearrangements essential for receptor dimerization and activation. Here we analyzed the crystal structures of VEGF-C in complex with VEGFR-3 domains D1-2 and of the VEGFR-3 D4-5 homodimer. The structures revealed a conserved ligand-binding interface in D2 and a unique mechanism for VEGFR dimerization and activation, with homotypic interactions in D5. Mutation of the conserved residues mediating the D5 interaction (Thr446 and Lys516) and the D7 interaction (Arg737) compromised VEGF-C induced VEGFR-3 activation. A thermodynamic analysis of VEGFR-3 deletion mutants showed that D3, D4-5, and D6-7 all contribute to ligand binding. A structural model of the VEGF-C/VEGFR-3 D1-7 complex derived from small-angle X-ray scattering data is consistent with the homotypic interactions in D5 and D7. Taken together, our data show that ligand-dependent homotypic interactions in D5 and D7 are essential for VEGFR activation, opening promising possibilities for the design of VEGFR-specific drugs.	+
-		+
-	Structural and mechanistic insights into VEGF receptor 3 ligand binding and activation.,Leppanen VM, Tvorogov D, Kisko K, Prota AE, Jeltsch M, Anisimov A, Markovic-Mueller S, Stuttfeld E, Goldie KN, Ballmer-Hofer K, Alitalo K Proc Natl Acad Sci U S A. 2013 Jul 22. PMID:23878260<ref>PMID:23878260</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 4bsj" style="background-color:#fffaf0;"></div~~>	+

	==See Also==		==See Also==
-	*[[~~Vascular Endothelial Growth Factor Receptor~~\|~~Vascular Endothelial Growth Factor Receptor~~]]	+	*[[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: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Receptor protein-tyrosine kinase]]~~	+	[[Category: Alitalo K]]
-	[[Category: Alitalo, K]]	+	[[Category: Anisimov A]]
-	[[Category: Anisimov, A]]	+	[[Category: Ballmer-Hofer K]]
-	[[Category: Ballmer-Hofer, K]]	+	[[Category: Goldie KN]]
-	[[Category: Goldie~~, K N~~]]	+	[[Category: Jeltsch M]]
-	[[Category: Jeltsch, M]]	+	[[Category: Kisko K]]
-	[[Category: Kisko, K]]	+	[[Category: Leppanen V-M]]
-	[[Category: Leppanen, V M]]	+	[[Category: Markovic-Mueller S]]
-	[[Category: Markovic-Mueller, S]]	+	[[Category: Prota AE]]
-	[[Category: Prota~~, A E~~]]	+	[[Category: Stuttfeld E]]
-	[[Category: Stuttfeld, E]]	+	[[Category: Tvorogov D]]
-	[[Category: Tvorogov, D]]	+
-	~~[[Category: Angiogenesis]]~~	+
-	~~[[Category: Dimerization]]~~	+
-	~~[[Category: Glycoprotein]]~~	+
-	~~[[Category: Ig domain]]~~	+
-	~~[[Category: Lymphangiogenesis]]~~	+
-	~~[[Category: Receptor tyrosine kinase]]~~	+
-	~~[[Category: Transferase]]~~	+
-	~~[[Category: Vascular~~]]	+

OCA at 07:26, 24 April 2019

OCA — Wed, 24 Apr 2019 07:26:19 GMT

←Older revision		Revision as of 07:26, 24 April 2019
Line 1:		Line 1:

	==Crystal structure of VEGFR-3 extracellular domains D4-5==		==Crystal structure of VEGFR-3 extracellular domains D4-5==
-	<StructureSection load='4bsj' size='340' side='right' caption='[[4bsj]], [[Resolution\|resolution]] 2.50Å' scene=''>	+	<StructureSection load='4bsj' size='340' side='right'caption='[[4bsj]], [[Resolution\|resolution]] 2.50Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4bsj]] is a 1 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=4BSJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BSJ FirstGlance]. <br>		<table><tr><td colspan='2'>[[4bsj]] is a 1 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=4BSJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BSJ FirstGlance]. <br>
Line 30:		Line 30:
	</StructureSection>		</StructureSection>
	[[Category: Human]]		[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]
	[[Category: Alitalo, K]]		[[Category: Alitalo, K]]

OCA at 12:42, 11 August 2016

OCA — Thu, 11 Aug 2016 12:42:38 GMT

←Older revision		Revision as of 12:42, 11 August 2016
Line 1:		Line 1:
		+
	==Crystal structure of VEGFR-3 extracellular domains D4-5==		==Crystal structure of VEGFR-3 extracellular domains D4-5==
	<StructureSection load='4bsj' size='340' side='right' caption='[[4bsj]], [[Resolution\|resolution]] 2.50Å' scene=''>		<StructureSection load='4bsj' size='340' side='right' caption='[[4bsj]], [[Resolution\|resolution]] 2.50Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4bsj]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Homo_sapiens Homo sapiens~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BSJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BSJ FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4bsj]] is a 1 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=4BSJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BSJ 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='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4bsk\|4bsk]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4bsk\|4bsk]]</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='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='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=4bsj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bsj OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4bsj RCSB], [http://www.ebi.ac.uk/pdbsum/4bsj PDBsum]</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=4bsj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bsj OCA], [http://pdbe.org/4bsj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4bsj RCSB], [http://www.ebi.ac.uk/pdbsum/4bsj PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4bsj ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 20:		Line 21:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
		+	<div class="pdbe-citations 4bsj" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
Line 27:		Line 29:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Homo sapiens~~]]	+	[[Category: Human]]
	[[Category: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]
	[[Category: Alitalo, K]]		[[Category: Alitalo, K]]

OCA at 12:43, 4 January 2015

OCA — Sun, 04 Jan 2015 12:43:20 GMT

←Older revision		Revision as of 12:43, 4 January 2015
Line 1:		Line 1:
-	~~{{STRUCTURE_4bsj\| PDB=4bsj \| SCENE= }}~~	+	==Crystal structure of VEGFR-3 extracellular domains D4-5==
-	===Crystal structure of VEGFR-3 extracellular domains D4-5===	+	<StructureSection load='4bsj' size='340' side='right' caption='[[4bsj]], [[Resolution\|resolution]] 2.50Å' scene=''>
-	~~{{ABSTRACT_PUBMED_23878260}}~~	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>[[4bsj]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BSJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BSJ FirstGlance]. <br>
-	==Disease==	+	</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>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4bsk\|4bsk]]</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='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=4bsj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bsj OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4bsj RCSB], [http://www.ebi.ac.uk/pdbsum/4bsj PDBsum]</span></td></tr>
		+	</table>
		+	== Disease ==
	[[http://www.uniprot.org/uniprot/VGFR3_HUMAN VGFR3_HUMAN]] Milroy disease. The disease is caused by mutations affecting the gene represented in this entry. Disease susceptibility is associated with variations affecting the gene represented in this entry. Plays an important role in tumor lymphangiogenesis, in cancer cell survival, migration, and formation of metastases.		[[http://www.uniprot.org/uniprot/VGFR3_HUMAN VGFR3_HUMAN]] Milroy disease. The disease is caused by mutations affecting the gene represented in this entry. Disease susceptibility is associated with variations affecting the gene represented in this entry. Plays an important role in tumor lymphangiogenesis, in cancer cell survival, migration, and formation of metastases.
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/VGFR3_HUMAN VGFR3_HUMAN]] Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFC and VEGFD, and plays an essential role in adult lymphangiogenesis and in the development of the vascular network and the cardiovascular system during embryonic development. Promotes proliferation, survival and migration of endothelial cells, and regulates angiogenic sprouting. Signaling by activated FLT4 leads to enhanced production of VEGFC, and to a lesser degree VEGFA, thereby creating a positive feedback loop that enhances FLT4 signaling. Modulates KDR signaling by forming heterodimers. The secreted isoform 3 may function as a decoy receptor for VEGFC and/or VEGFD and play an important role as a negative regulator of VEGFC-mediated lymphangiogenesis and angiogenesis. Binding of vascular growth factors to isoform 1 or isoform 2 leads to the activation of several signaling cascades; isoform 2 seems to be less efficient in signal transduction, because it has a truncated C-terminus and therefore lacks several phosphorylation sites. Mediates activation of the MAPK1/ERK2, MAPK3/ERK1 signaling pathway, of MAPK8 and the JUN signaling pathway, and of the AKT1 signaling pathway. Phosphorylates SHC1. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Promotes phosphorylation of MAPK8 at 'Thr-183' and 'Tyr-185', and of AKT1 at 'Ser-473'.<ref>PMID:8700872</ref> <ref>PMID:7675451</ref> <ref>PMID:9435229</ref> <ref>PMID:11532940</ref> <ref>PMID:15474514</ref> <ref>PMID:15102829</ref> <ref>PMID:16076871</ref> <ref>PMID:16452200</ref> <ref>PMID:17210781</ref> <ref>PMID:19779139</ref> <ref>PMID:19610651</ref> <ref>PMID:20431062</ref> <ref>PMID:20224550</ref> <ref>PMID:20445537</ref> <ref>PMID:21273538</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are key drivers of blood and lymph vessel formation in development, but also in several pathological processes. VEGF-C signaling through VEGFR-3 promotes lymphangiogenesis, which is a clinically relevant target for treating lymphatic insufficiency and for blocking tumor angiogenesis and metastasis. The extracellular domain of VEGFRs consists of seven Ig homology domains; domains 1-3 (D1-3) are responsible for ligand binding, and the membrane-proximal domains 4-7 (D4-7) are involved in structural rearrangements essential for receptor dimerization and activation. Here we analyzed the crystal structures of VEGF-C in complex with VEGFR-3 domains D1-2 and of the VEGFR-3 D4-5 homodimer. The structures revealed a conserved ligand-binding interface in D2 and a unique mechanism for VEGFR dimerization and activation, with homotypic interactions in D5. Mutation of the conserved residues mediating the D5 interaction (Thr446 and Lys516) and the D7 interaction (Arg737) compromised VEGF-C induced VEGFR-3 activation. A thermodynamic analysis of VEGFR-3 deletion mutants showed that D3, D4-5, and D6-7 all contribute to ligand binding. A structural model of the VEGF-C/VEGFR-3 D1-7 complex derived from small-angle X-ray scattering data is consistent with the homotypic interactions in D5 and D7. Taken together, our data show that ligand-dependent homotypic interactions in D5 and D7 are essential for VEGFR activation, opening promising possibilities for the design of VEGFR-specific drugs.

-	~~==Function==~~	+	Structural and mechanistic insights into VEGF receptor 3 ligand binding and activation.,Leppanen VM, Tvorogov D, Kisko K, Prota AE, Jeltsch M, Anisimov A, Markovic-Mueller S, Stuttfeld E, Goldie KN, Ballmer-Hofer K, Alitalo K Proc Natl Acad Sci U S A. 2013 Jul 22. PMID:23878260<ref>PMID:23878260</ref>
-	~~[[http://www.uniprot.org/uniprot/VGFR3_HUMAN VGFR3_HUMAN]] Tyrosine-protein kinase that acts as a cell-surface~~ receptor ~~for VEGFC~~ and ~~VEGFD, and plays an essential role in adult lymphangiogenesis and in the development of the vascular network and the cardiovascular system during embryonic development~~. ~~Promotes proliferation~~, ~~survival and migration of endothelial cells~~, ~~and regulates angiogenic sprouting. Signaling by activated FLT4 leads to enhanced production of VEGFC~~, ~~and to a lesser degree VEGFA~~, thereby creating a positive feedback loop that enhances FLT4 signaling. Modulates KDR signaling by forming heterodimers. The secreted isoform 3 may function as a decoy receptor for VEGFC and/or VEGFD and play an important role as a negative regulator of VEGFC-mediated lymphangiogenesis and angiogenesis. Binding of vascular growth factors to isoform 1 or isoform 2 leads to the activation of several signaling cascades; isoform 2 seems to be less efficient in signal transduction, ~~because it has a truncated C~~-~~terminus and therefore lacks several phosphorylation sites. Mediates activation of the MAPK1/ERK2~~, ~~MAPK3/ERK1 signaling pathway~~, ~~of MAPK8 and the JUN signaling pathway~~, ~~and of the AKT1 signaling pathway. Phosphorylates SHC1. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3~~-~~kinase~~. ~~Promotes phosphorylation of MAPK8 at 'Thr-183' and 'Tyr-185', and of AKT1 at 'Ser-473'~~.~~<ref>~~PMID:8700872</ref> <ref>PMID:7675451</ref> <ref>PMID:9435229</ref> <ref>PMID:11532940</ref> <ref>PMID:15474514</ref> <ref>PMID:15102829</ref> <ref>PMID:16076871</ref> <ref>PMID:16452200</ref> <ref>PMID:17210781</ref> <ref>PMID:19779139</ref> <ref>PMID:19610651</ref> <ref>PMID:20431062</ref> <ref>PMID:20224550</ref> <ref>PMID:20445537</ref> <ref>PMID:~~21273538~~</ref>	+

-	~~==About this Structure==~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[4bsj]] is~~ a ~~1 chain structure with sequence from [http://en~~.~~wikipedia~~.~~org/wiki/Homo_sapiens Homo sapiens]~~. ~~Full crystallographic information is available from [http:~~/~~/oca.weizmann.ac.il/oca-bin/ocashort?id=4BSJ OCA].~~	+	</div>

-	==~~Reference~~==	+	==See Also==
-	~~<ref group~~=~~"xtra">PMID:023878260</ref>~~<references ~~group="xtra"~~/><~~references~~/>	+	*[[Vascular Endothelial Growth Factor Receptor\|Vascular Endothelial Growth Factor Receptor]]
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]
-	[[Category: Alitalo, K.]]	+	[[Category: Alitalo, K]]
-	[[Category: Anisimov, A.]]	+	[[Category: Anisimov, A]]
-	[[Category: Ballmer-Hofer, K.]]	+	[[Category: Ballmer-Hofer, K]]
-	[[Category: Goldie, K N.]]	+	[[Category: Goldie, K N]]
-	[[Category: Jeltsch, M.]]	+	[[Category: Jeltsch, M]]
-	[[Category: Kisko, K.]]	+	[[Category: Kisko, K]]
-	[[Category: Leppanen, V M.]]	+	[[Category: Leppanen, V M]]
-	[[Category: Markovic-Mueller, S.]]	+	[[Category: Markovic-Mueller, S]]
-	[[Category: Prota, A E.]]	+	[[Category: Prota, A E]]
-	[[Category: Stuttfeld, E.]]	+	[[Category: Stuttfeld, E]]
-	[[Category: Tvorogov, D.]]	+	[[Category: Tvorogov, D]]
	[[Category: Angiogenesis]]		[[Category: Angiogenesis]]
	[[Category: Dimerization]]		[[Category: Dimerization]]

OCA at 05:13, 1 August 2013

OCA — Thu, 01 Aug 2013 05:13:34 GMT

←Older revision		Revision as of 05:13, 1 August 2013
Line 1:		Line 1:
-	~~'''Unreleased~~ structure~~'''~~	+	{{STRUCTURE_4bsj\| PDB=4bsj \| SCENE= }}
		+	===Crystal structure of VEGFR-3 extracellular domains D4-5===
		+	{{ABSTRACT_PUBMED_23878260}}

-	The entry ~~4bsj~~ is ~~ON HOLD~~ ~~until Paper Publication~~	+	==Disease==
		+	[[http://www.uniprot.org/uniprot/VGFR3_HUMAN VGFR3_HUMAN]] Milroy disease. The disease is caused by mutations affecting the gene represented in this entry. Disease susceptibility is associated with variations affecting the gene represented in this entry. Plays an important role in tumor lymphangiogenesis, in cancer cell survival, migration, and formation of metastases.

-	~~Authors~~: ~~Leppanen, V~~.-M., ~~Tvorogov, D~~., ~~Kisko~~, K., ~~Prota~~, A.E.~~, Jeltsch, M~~., ~~Anisimov, A., Markovic~~-~~Mueller, S~~., ~~Stuttfeld~~, ~~E., Goldie~~, K.N., ~~Ballmer~~-~~Hofer, K~~., ~~Alitalo, K~~.	+	==Function==
		+	[[http://www.uniprot.org/uniprot/VGFR3_HUMAN VGFR3_HUMAN]] Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFC and VEGFD, and plays an essential role in adult lymphangiogenesis and in the development of the vascular network and the cardiovascular system during embryonic development. Promotes proliferation, survival and migration of endothelial cells, and regulates angiogenic sprouting. Signaling by activated FLT4 leads to enhanced production of VEGFC, and to a lesser degree VEGFA, thereby creating a positive feedback loop that enhances FLT4 signaling. Modulates KDR signaling by forming heterodimers. The secreted isoform 3 may function as a decoy receptor for VEGFC and/or VEGFD and play an important role as a negative regulator of VEGFC-mediated lymphangiogenesis and angiogenesis. Binding of vascular growth factors to isoform 1 or isoform 2 leads to the activation of several signaling cascades; isoform 2 seems to be less efficient in signal transduction, because it has a truncated C-terminus and therefore lacks several phosphorylation sites. Mediates activation of the MAPK1/ERK2, MAPK3/ERK1 signaling pathway, of MAPK8 and the JUN signaling pathway, and of the AKT1 signaling pathway. Phosphorylates SHC1. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Promotes phosphorylation of MAPK8 at 'Thr-183' and 'Tyr-185', and of AKT1 at 'Ser-473'.<ref>PMID:8700872</ref> <ref>PMID:7675451</ref> <ref>PMID:9435229</ref> <ref>PMID:11532940</ref> <ref>PMID:15474514</ref> <ref>PMID:15102829</ref> <ref>PMID:16076871</ref> <ref>PMID:16452200</ref> <ref>PMID:17210781</ref> <ref>PMID:19779139</ref> <ref>PMID:19610651</ref> <ref>PMID:20431062</ref> <ref>PMID:20224550</ref> <ref>PMID:20445537</ref> <ref>PMID:21273538</ref>

-	~~Description: Crystal~~ structure ~~of VEGFR~~-~~3 extracellular domains D4~~-5	+	==About this Structure==
		+	[[4bsj]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BSJ OCA].
		+
		+	==Reference==
		+	<ref group="xtra">PMID:023878260</ref><references group="xtra"/><references/>
		+	[[Category: Homo sapiens]]
		+	[[Category: Receptor protein-tyrosine kinase]]
		+	[[Category: Alitalo, K.]]
		+	[[Category: Anisimov, A.]]
		+	[[Category: Ballmer-Hofer, K.]]
		+	[[Category: Goldie, K N.]]
		+	[[Category: Jeltsch, M.]]
		+	[[Category: Kisko, K.]]
		+	[[Category: Leppanen, V M.]]
		+	[[Category: Markovic-Mueller, S.]]
		+	[[Category: Prota, A E.]]
		+	[[Category: Stuttfeld, E.]]
		+	[[Category: Tvorogov, D.]]
		+	[[Category: Angiogenesis]]
		+	[[Category: Dimerization]]
		+	[[Category: Glycoprotein]]
		+	[[Category: Ig domain]]
		+	[[Category: Lymphangiogenesis]]
		+	[[Category: Receptor tyrosine kinase]]
		+	[[Category: Transferase]]
		+	[[Category: Vascular]]

OCA at 08:28, 30 June 2013

OCA — Sun, 30 Jun 2013 08:28:35 GMT

←Older revision		Revision as of 08:28, 30 June 2013
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 4bsj is ON HOLD	+	The entry 4bsj is ON HOLD until Paper Publication

	Authors: Leppanen, V.-M., Tvorogov, D., Kisko, K., Prota, A.E., Jeltsch, M., Anisimov, A., Markovic-Mueller, S., Stuttfeld, E., Goldie, K.N., Ballmer-Hofer, K., Alitalo, K.		Authors: Leppanen, V.-M., Tvorogov, D., Kisko, K., Prota, A.E., Jeltsch, M., Anisimov, A., Markovic-Mueller, S., Stuttfeld, E., Goldie, K.N., Ballmer-Hofer, K., Alitalo, K.

	Description: Crystal structure of VEGFR-3 extracellular domains D4-5		Description: Crystal structure of VEGFR-3 extracellular domains D4-5

OCA: Protected "4bsj" [edit=sysop:move=sysop]

OCA — Wed, 19 Jun 2013 10:57:39 GMT

Protected "4bsj" [edit=sysop:move=sysop]

←Older revision

Revision as of 10:57, 19 June 2013

OCA: New page: '''Unreleased structure''' The entry 4bsj is ON HOLD Authors: Leppanen, V.-M., Tvorogov, D., Kisko, K., Prota, A.E., Jeltsch, M., Anisimov, A., Markovic-Mueller, S., Stuttfeld, E., Gold...

OCA — Wed, 19 Jun 2013 10:57:37 GMT

New page: '''Unreleased structure''' The entry 4bsj is ON HOLD Authors: Leppanen, V.-M., Tvorogov, D., Kisko, K., Prota, A.E., Jeltsch, M., Anisimov, A., Markovic-Mueller, S., Stuttfeld, E., Gold...

New page

'''Unreleased structure'''

The entry 4bsj is ON HOLD

Authors: Leppanen, V.-M., Tvorogov, D., Kisko, K., Prota, A.E., Jeltsch, M., Anisimov, A., Markovic-Mueller, S., Stuttfeld, E., Goldie, K.N., Ballmer-Hofer, K., Alitalo, K.

Description: Crystal structure of VEGFR-3 extracellular domains D4-5