View source for 6fnj


==Crystal Structure of Ephrin B4 (EphB4) Receptor Protein Kinase with an isomer of NVP-BHG712==
<StructureSection load='6fnj' size='340' side='right' caption='[[6fnj]], [[Resolution|resolution]] 1.24&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6fnj]] is a 2 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=6FNJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FNJ FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DWT:4-methyl-3-[(2-methyl-6-pyridin-3-yl-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-~{N}-[3-(trifluoromethyl)phenyl]benzamide'>DWT</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">EPHB4, HTK, MYK1, TYRO11 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6fnj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fnj OCA], [http://pdbe.org/6fnj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6fnj RCSB], [http://www.ebi.ac.uk/pdbsum/6fnj PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6fnj ProSAT]</span></td></tr>
</table>
== 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>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Erythropoietin-producing hepatocellular (EPH) receptors are transmembrane receptor tyrosine kinases. Their extracellular domains bind specifically to ephrin A/B ligands, and this binding modulates intracellular kinase activity. EPHs are key players in bidirectional intercellular signaling, controlling cell morphology, adhesion, and migration. They are increasingly recognized as cancer drug targets. We analyzed the binding of NVP-BHG712 (NVP) to EPHA2 and EPHB4. Unexpectedly, all tested commercially available NVP samples turned out to be a regioisomer (NVPiso) of the inhibitor, initially described in a Novartis patent application. They only differ by the localization of a single methyl group on either one of two adjacent nitrogen atoms. The two compounds of identical mass revealed different binding modes. Furthermore, both in vitro and in vivo experiments showed that the isomers differ in their kinase affinity and selectivity.

NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family.,Troster A, Heinzlmeir S, Berger BT, Gande SL, Saxena K, Sreeramulu S, Linhard V, Nasiri AH, Bolte M, Muller S, Kuster B, Medard G, Kudlinzki D, Schwalbe H ChemMedChem. 2018 Jun 21. doi: 10.1002/cmdc.201800398. PMID:29928781<ref>PMID:29928781</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6fnj" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Receptor protein-tyrosine kinase]]
[[Category: Kudlinzki, D]]
[[Category: Linhard, V L]]
[[Category: Saxena, K]]
[[Category: Schwalbe, H]]
[[Category: Troester, A]]
[[Category: Witt, K]]
[[Category: Complex]]
[[Category: Inhibitor]]
[[Category: Protein tyrosine kinase]]
[[Category: Transferase]]