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| | ==ephB4 kinase domain inhibitor complex== | | ==ephB4 kinase domain inhibitor complex== |
| - | <StructureSection load='4bb4' size='340' side='right' caption='[[4bb4]], [[Resolution|resolution]] 1.65Å' scene=''> | + | <StructureSection load='4bb4' size='340' side='right'caption='[[4bb4]], [[Resolution|resolution]] 1.65Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4bb4]] 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=4BB4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BB4 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4bb4]] 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=4BB4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BB4 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=32W:N-(2-METHOXYETHYL)-4-[(6-PYRIDIN-4-YLQUINAZOLIN-2-YL)AMINO]BENZAMIDE'>32W</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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]] 1.65Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2bba|2bba]], [[2vwu|2vwu]], [[2vwv|2vwv]], [[2vww|2vww]], [[2vwx|2vwx]], [[2vwy|2vwy]], [[2vwz|2vwz]], [[2vx0|2vx0]], [[2vx1|2vx1]], [[2x9f|2x9f]], [[2xvd|2xvd]], [[4aw5|4aw5]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=32W:N-(2-METHOXYETHYL)-4-[(6-PYRIDIN-4-YLQUINAZOLIN-2-YL)AMINO]BENZAMIDE'>32W</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=4bb4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bb4 OCA], [https://pdbe.org/4bb4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bb4 RCSB], [https://www.ebi.ac.uk/pdbsum/4bb4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bb4 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=4bb4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bb4 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4bb4 RCSB], [http://www.ebi.ac.uk/pdbsum/4bb4 PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/EPHB4_HUMAN EPHB4_HUMAN]] Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Together with its cognate ligand/functional ligand EFNB2 plays a central role in heart morphogenesis and angiogenesis through regulation of cell adhesion and cell migration. EPHB4-mediated forward signaling controls cellular repulsion and segregation form EFNB2-expressing cells. Plays also a role in postnatal blood vessel remodeling, morphogenesis and permeability and is thus important in the context of tumor angiogenesis.<ref>PMID:12734395</ref> <ref>PMID:16424904</ref> | + | [https://www.uniprot.org/uniprot/EPHB4_HUMAN EPHB4_HUMAN] Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Together with its cognate ligand/functional ligand EFNB2 plays a central role in heart morphogenesis and angiogenesis through regulation of cell adhesion and cell migration. EPHB4-mediated forward signaling controls cellular repulsion and segregation form EFNB2-expressing cells. Plays also a role in postnatal blood vessel remodeling, morphogenesis and permeability and is thus important in the context of tumor angiogenesis.<ref>PMID:12734395</ref> <ref>PMID:16424904</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | 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 4bb4" style="background-color:#fffaf0;"></div> |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Ephrin receptor|Ephrin receptor]] | + | *[[Ephrin receptor 3D structures|Ephrin receptor 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Receptor protein-tyrosine kinase]] | + | [[Category: Large Structures]] |
| - | [[Category: Brassington, C A]] | + | [[Category: Brassington CA]] |
| - | [[Category: Green, I]] | + | [[Category: Green I]] |
| - | [[Category: McCall, E J]] | + | [[Category: McCall EJ]] |
| - | [[Category: Read, J]] | + | [[Category: Read J]] |
| - | [[Category: Valentine, A L]] | + | [[Category: Valentine AL]] |
| - | [[Category: Transferase]]
| + | |
| - | [[Category: Unphosphorylated]]
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| Structural highlights
Function
EPHB4_HUMAN Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Together with its cognate ligand/functional ligand EFNB2 plays a central role in heart morphogenesis and angiogenesis through regulation of cell adhesion and cell migration. EPHB4-mediated forward signaling controls cellular repulsion and segregation form EFNB2-expressing cells. Plays also a role in postnatal blood vessel remodeling, morphogenesis and permeability and is thus important in the context of tumor angiogenesis.[1] [2]
Publication Abstract from PubMed
B-Raf represents an attractive target for anti-cancer therapy and the development of small molecule B-Raf inhibitors has delivered new therapies for metastatic melanoma patients. We have discovered a novel class of small molecules that inhibit mutant B-RafV600E kinase activity both in vitro and in vivo. Investigations into the SAR of the series are presented along with efforts to improve upon the cellular potency, solubility, and pharmacokinetic profile. Compounds selectively inhibited B-RafV600E in vitro and showed preferential anti-proliferative activity in mutant B-RafV600E cell lines and exhibited selectivity in a kinase panel against other kinases. Examples from this series inhibit growth of a B-RafV600E A375 xenograft in vivo at a well tolerated dose. In addition, aminoquinazolines described herein were shown to display pERK elevation in non-mutant B-Raf cell lines in vitro.
Discovery and Optimization of a Novel Series of Potent Mutant B-Raf V600E Selective Kinase Inhibitors.,Vasbinder MM, Aquila B, Augustin M, Chen H, Cheung T, Cook D, Drew L, Fauber BP, Glossop S, Grondine M, Hennessy EJ, Johannes J, Lee S, Lyne PD, Mortl M, Omer C, Palakurthi S, Pontz T, Read J, Sha L, Shen M, Steinbacher S, Wang H, Wu A, Ye M J Med Chem. 2013 Feb 11. PMID:23398453[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Fuller T, Korff T, Kilian A, Dandekar G, Augustin HG. Forward EphB4 signaling in endothelial cells controls cellular repulsion and segregation from ephrinB2 positive cells. J Cell Sci. 2003 Jun 15;116(Pt 12):2461-70. Epub 2003 May 6. PMID:12734395 doi:10.1242/jcs.00426
- ↑ Erber R, Eichelsbacher U, Powajbo V, Korn T, Djonov V, Lin J, Hammes HP, Grobholz R, Ullrich A, Vajkoczy P. EphB4 controls blood vascular morphogenesis during postnatal angiogenesis. EMBO J. 2006 Feb 8;25(3):628-41. Epub 2006 Jan 19. PMID:16424904 doi:10.1038/sj.emboj.7600949
- ↑ Vasbinder MM, Aquila B, Augustin M, Chen H, Cheung T, Cook D, Drew L, Fauber BP, Glossop S, Grondine M, Hennessy EJ, Johannes J, Lee S, Lyne PD, Mortl M, Omer C, Palakurthi S, Pontz T, Read J, Sha L, Shen M, Steinbacher S, Wang H, Wu A, Ye M. Discovery and Optimization of a Novel Series of Potent Mutant B-Raf V600E Selective Kinase Inhibitors. J Med Chem. 2013 Feb 11. PMID:23398453 doi:http://dx.doi.org/10.1021/jm301658d
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