2oh4

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{{STRUCTURE_2oh4| PDB=2oh4 | SCENE= }}
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==Crystal structure of Vegfr2 with a benzimidazole-urea inhibitor==
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===Crystal structure of Vegfr2 with a benzimidazole-urea inhibitor===
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<StructureSection load='2oh4' size='340' side='right' caption='[[2oh4]], [[Resolution|resolution]] 2.05&Aring;' scene=''>
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{{ABSTRACT_PUBMED_17676829}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2oh4]] 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=2OH4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2OH4 FirstGlance]. <br>
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</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GIG:METHYL+(5-{4-[({[2-FLUORO-5-(TRIFLUOROMETHYL)PHENYL]AMINO}CARBONYL)AMINO]PHENOXY}-1H-BENZIMIDAZOL-2-YL)CARBAMATE'>GIG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene><br>
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<tr><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>
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<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1vr2|1vr2]], [[1y6a|1y6a]], [[1y6b|1y6b]], [[1ywm|1ywm]]</td></tr>
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<tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">KDR, FLK1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
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<tr><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>
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<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2oh4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2oh4 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2oh4 RCSB], [http://www.ebi.ac.uk/pdbsum/2oh4 PDBsum]</span></td></tr>
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<table>
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== Disease ==
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[[http://www.uniprot.org/uniprot/VGFR2_HUMAN VGFR2_HUMAN]] Defects in KDR are associated with susceptibility to hemangioma capillary infantile (HCI) [MIM:[http://omim.org/entry/602089 602089]]. HCI are benign, highly proliferative lesions involving aberrant localized growth of capillary endothelium. They are the most common tumor of infancy, occurring in up to 10% of all births. Hemangiomas tend to appear shortly after birth and show rapid neonatal growth for up to 12 months characterized by endothelial hypercellularity and increased numbers of mast cells. This phase is followed by slow involution at a rate of about 10% per year and replacement by fibrofatty stroma.<ref>PMID:11807987</ref> <ref>PMID:18931684</ref> Note=Plays a major role in tumor angiogenesis. In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions.
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== Function ==
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[[http://www.uniprot.org/uniprot/VGFR2_HUMAN VGFR2_HUMAN]] Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD. Plays an essential role in the regulation of angiogenesis, vascular development, vascular permeability, and embryonic hematopoiesis. Promotes proliferation, survival, migration and differentiation of endothelial cells. Promotes reorganization of the actin cytoskeleton. Isoforms lacking a transmembrane domain, such as isoform 2 and isoform 3, may function as decoy receptors for VEGFA, VEGFC and/or VEGFD. Isoform 2 plays an important role as negative regulator of VEGFA- and VEGFC-mediated lymphangiogenesis by limiting the amount of free VEGFA and/or VEGFC and preventing their binding to FLT4. Modulates FLT1 and FLT4 signaling by forming heterodimers. Binding of vascular growth factors to isoform 1 leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, reorganization of the actin cytoskeleton and activation of PTK2/FAK1. Required for VEGFA-mediated induction of NOS2 and NOS3, leading to the production of the signaling molecule nitric oxide (NO) by endothelial cells. Phosphorylates PLCG1. Promotes phosphorylation of FYN, NCK1, NOS3, PIK3R1, PTK2/FAK1 and SRC.<ref>PMID:19668192</ref> <ref>PMID:1417831</ref> <ref>PMID:7929439</ref> <ref>PMID:9160888</ref> <ref>PMID:9837777</ref> <ref>PMID:9804796</ref> <ref>PMID:10600473</ref> <ref>PMID:10102632</ref> <ref>PMID:11387210</ref> <ref>PMID:12649282</ref> <ref>PMID:15026417</ref> <ref>PMID:15215251</ref> <ref>PMID:15962004</ref> <ref>PMID:16966330</ref> <ref>PMID:17303569</ref> <ref>PMID:19834490</ref> <ref>PMID:20179233</ref> <ref>PMID:20224550</ref> <ref>PMID:20705758</ref> <ref>PMID:10368301</ref> <ref>PMID:18529047</ref> <ref>PMID:20080685</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/oh/2oh4_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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We herein disclose a novel chemical series of benzimidazole-ureas as inhibitors of VEGFR-2 and TIE-2 kinase receptors, both of which are implicated in angiogenesis. Structure-activity relationship (SAR) studies elucidated a critical role for the N1 nitrogen of both the benzimidazole (segment E) and urea (segment B) moieties. The SAR results were also supported by the X-ray crystallographic elucidation of the role of the N1 nitrogen and the urea moiety when the benzimidazole-urea compounds were bound to the VEGFR-2 enzyme. The left side phenyl ring (segment A) occupies the backpocket where a 3-hydrophobic substituent was favored for TIE-2 activity.
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==Disease==
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Discovery of novel benzimidazoles as potent inhibitors of TIE-2 and VEGFR-2 tyrosine kinase receptors.,Hasegawa M, Nishigaki N, Washio Y, Kano K, Harris PA, Sato H, Mori I, West RI, Shibahara M, Toyoda H, Wang L, Nolte RT, Veal JM, Cheung M J Med Chem. 2007 Sep 6;50(18):4453-70. Epub 2007 Aug 4. PMID:17676829<ref>PMID:17676829</ref>
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[[http://www.uniprot.org/uniprot/VGFR2_HUMAN VGFR2_HUMAN]] Defects in KDR are associated with susceptibility to hemangioma capillary infantile (HCI) [MIM:[http://omim.org/entry/602089 602089]]. HCI are benign, highly proliferative lesions involving aberrant localized growth of capillary endothelium. They are the most common tumor of infancy, occurring in up to 10% of all births. Hemangiomas tend to appear shortly after birth and show rapid neonatal growth for up to 12 months characterized by endothelial hypercellularity and increased numbers of mast cells. This phase is followed by slow involution at a rate of about 10% per year and replacement by fibrofatty stroma.<ref>PMID:11807987</ref><ref>PMID:18931684</ref> Note=Plays a major role in tumor angiogenesis. In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions.
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==Function==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[http://www.uniprot.org/uniprot/VGFR2_HUMAN VGFR2_HUMAN]] Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD. Plays an essential role in the regulation of angiogenesis, vascular development, vascular permeability, and embryonic hematopoiesis. Promotes proliferation, survival, migration and differentiation of endothelial cells. Promotes reorganization of the actin cytoskeleton. Isoforms lacking a transmembrane domain, such as isoform 2 and isoform 3, may function as decoy receptors for VEGFA, VEGFC and/or VEGFD. Isoform 2 plays an important role as negative regulator of VEGFA- and VEGFC-mediated lymphangiogenesis by limiting the amount of free VEGFA and/or VEGFC and preventing their binding to FLT4. Modulates FLT1 and FLT4 signaling by forming heterodimers. Binding of vascular growth factors to isoform 1 leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, reorganization of the actin cytoskeleton and activation of PTK2/FAK1. Required for VEGFA-mediated induction of NOS2 and NOS3, leading to the production of the signaling molecule nitric oxide (NO) by endothelial cells. Phosphorylates PLCG1. Promotes phosphorylation of FYN, NCK1, NOS3, PIK3R1, PTK2/FAK1 and SRC.<ref>PMID:19668192</ref><ref>PMID:1417831</ref><ref>PMID:7929439</ref><ref>PMID:9160888</ref><ref>PMID:9837777</ref><ref>PMID:9804796</ref><ref>PMID:10600473</ref><ref>PMID:10102632</ref><ref>PMID:11387210</ref><ref>PMID:12649282</ref><ref>PMID:15026417</ref><ref>PMID:15215251</ref><ref>PMID:15962004</ref><ref>PMID:16966330</ref><ref>PMID:17303569</ref><ref>PMID:19834490</ref><ref>PMID:20179233</ref><ref>PMID:20224550</ref><ref>PMID:20705758</ref><ref>PMID:10368301</ref><ref>PMID:18529047</ref><ref>PMID:20080685</ref>
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</div>
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==About this Structure==
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[[2oh4]] 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=2OH4 OCA].
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==See Also==
==See Also==
*[[Vascular Endothelial Growth Factor Receptor|Vascular Endothelial Growth Factor Receptor]]
*[[Vascular Endothelial Growth Factor Receptor|Vascular Endothelial Growth Factor Receptor]]
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:017676829</ref><references group="xtra"/><references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Receptor protein-tyrosine kinase]]
[[Category: Receptor protein-tyrosine kinase]]

Revision as of 18:23, 30 September 2014

Crystal structure of Vegfr2 with a benzimidazole-urea inhibitor

2oh4, resolution 2.05Å

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