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6fnk

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Revision as of 08:01, 29 August 2018

Crystal Structure of Ephrin B4 (EphB4) Receptor Protein Kinase with a pyrazolo[3,4-d]pyrimidine fragment of NVP-BHG712

Structural highlights

6fnk is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Gene:	EPHB4, HTK, MYK1, TYRO11 (HUMAN)
Activity:	Receptor protein-tyrosine kinase, with EC number 2.7.10.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

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^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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
↑ 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. NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. ChemMedChem. 2018 Jun 21. doi: 10.1002/cmdc.201800398. PMID:29928781 doi:http://dx.doi.org/10.1002/cmdc.201800398

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6fnk"

@@ Line 3: / Line 3: @@
 <StructureSection load='6fnk' size='340' side='right' caption='[[6fnk]], [[Resolution|resolution]] 1.05&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6fnk]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FNK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FNK FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6fnk]] 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=6FNK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FNK FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DXK:1-methyl-6-pyridin-3-yl-pyrazolo[3,4-d]pyrimidin-4-amine'>DXK</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=6fnk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fnk OCA], [http://pdbe.org/6fnk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6fnk RCSB], [http://www.ebi.ac.uk/pdbsum/6fnk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6fnk ProSAT]</span></td></tr>
@@ Line 23: / Line 24: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Receptor protein-tyrosine kinase]]
 [[Category: KUDLINZKI, D]]

6fnk

From Proteopedia

Revision as of 08:01, 29 August 2018

Crystal Structure of Ephrin B4 (EphB4) Receptor Protein Kinase with a pyrazolo[3,4-d]pyrimidine fragment of NVP-BHG712

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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