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2y6o

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Revision as of 16:36, 5 August 2016

Crystal structure of EphA4 kinase domain in complex with Dasatinib.

Structural highlights

2y6o is a 1 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	2y6m, 2xyu, 1b0x
Activity:	Receptor protein-tyrosine kinase, with EC number 2.7.10.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[EPHA4_MOUSE] Receptor tyrosine kinase which binds membrane-bound ephrin 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. Highly promiscuous, it has the unique property among Eph receptors to bind and to be physiologically activated by both GPI-anchored ephrin-A and transmembrane ephrin-B ligands including EFNA1 and EFNB3. Upon activation by ephrin ligands, modulates cell morphology and integrin-dependent cell adhesion through regulation of the Rac, Rap and Rho GTPases activity. Plays an important role in the development of the nervous system controlling different steps of axonal guidance including the establishment of the corticospinal projections. May also control the segregation of motor and sensory axons during neuromuscular circuit development. Beside its role in axonal guidance plays a role in synaptic plasticity. Activated by EFNA1 phosphorylates CDK5 at 'Tyr-15' which in turn phosphorylates NGEF regulating RHOA and dendritic spine morphogenesis. In the nervous system, plays also a role in repair after injury preventing axonal regeneration and in angiogenesis playing a role in central nervous system vascular formation. Additionally, its promiscuity makes it available to participate in a variety of cell-cell signaling regulating for instance the development of the thymic epithelium.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9]

Publication Abstract from PubMed

The Eph family of receptor tyrosine kinases regulates diverse cellular processes while the over-expression of a member of this family, EphA4, has been reported in a variety of malignant carcinomas. To gain insight into molecular mechanisms and to facilitate structure-based inhibitor design, we solved the crystal structure of the native EphA4 kinase domain in both the apo and dasatinib bound forms. Analysis of the two structures provides insight into structural features of inhibitor binding and revealed a hydrophobic back-pocket in the ATP- binding site of EphA4 which was previously unidentified. The structures suggest a route towards development of novel and specific inhibitors.

Crystal structure of the EphA4 protein tyrosine kinase domain in the apo- and dasatinib-bound state.,Farenc C, Celie PH, Tensen CP, de Esch IJ, Siegal G FEBS Lett. 2011 Oct 22. PMID:22036717^[10]

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

References

↑ Dottori M, Hartley L, Galea M, Paxinos G, Polizzotto M, Kilpatrick T, Bartlett PF, Murphy M, Kontgen F, Boyd AW. EphA4 (Sek1) receptor tyrosine kinase is required for the development of the corticospinal tract. Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13248-53. PMID:9789074
↑ Goldshmit Y, Galea MP, Wise G, Bartlett PF, Turnley AM. Axonal regeneration and lack of astrocytic gliosis in EphA4-deficient mice. J Neurosci. 2004 Nov 10;24(45):10064-73. PMID:15537875 doi:http://dx.doi.org/10.1523/JNEUROSCI.2981-04.2004
↑ Goldshmit Y, Galea MP, Bartlett PF, Turnley AM. EphA4 regulates central nervous system vascular formation. J Comp Neurol. 2006 Aug 20;497(6):864-75. PMID:16802330 doi:http://dx.doi.org/10.1002/cne.21029
↑ Munoz JJ, Alfaro D, Garcia-Ceca J, Alonso-C LM, Jimenez E, Zapata A. Thymic alterations in EphA4-deficient mice. J Immunol. 2006 Jul 15;177(2):804-13. PMID:16818734
↑ Iwasato T, Katoh H, Nishimaru H, Ishikawa Y, Inoue H, Saito YM, Ando R, Iwama M, Takahashi R, Negishi M, Itohara S. Rac-GAP alpha-chimerin regulates motor-circuit formation as a key mediator of EphrinB3/EphA4 forward signaling. Cell. 2007 Aug 24;130(4):742-53. PMID:17719550 doi:http://dx.doi.org/10.1016/j.cell.2007.07.022
↑ Richter M, Murai KK, Bourgin C, Pak DT, Pasquale EB. The EphA4 receptor regulates neuronal morphology through SPAR-mediated inactivation of Rap GTPases. J Neurosci. 2007 Dec 19;27(51):14205-15. PMID:18094260 doi:http://dx.doi.org/10.1523/JNEUROSCI.2746-07.2007
↑ Fu WY, Chen Y, Sahin M, Zhao XS, Shi L, Bikoff JB, Lai KO, Yung WH, Fu AK, Greenberg ME, Ip NY. Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism. Nat Neurosci. 2007 Jan;10(1):67-76. Epub 2006 Dec 3. PMID:17143272 doi:10.1038/nn1811
↑ Beg AA, Sommer JE, Martin JH, Scheiffele P. alpha2-Chimaerin is an essential EphA4 effector in the assembly of neuronal locomotor circuits. Neuron. 2007 Sep 6;55(5):768-78. PMID:17785183 doi:http://dx.doi.org/10.1016/j.neuron.2007.07.036
↑ Gallarda BW, Bonanomi D, Muller D, Brown A, Alaynick WA, Andrews SE, Lemke G, Pfaff SL, Marquardt T. Segregation of axial motor and sensory pathways via heterotypic trans-axonal signaling. Science. 2008 Apr 11;320(5873):233-6. doi: 10.1126/science.1153758. PMID:18403711 doi:http://dx.doi.org/10.1126/science.1153758
↑ Farenc C, Celie PH, Tensen CP, de Esch IJ, Siegal G. Crystal structure of the EphA4 protein tyrosine kinase domain in the apo- and dasatinib-bound state. FEBS Lett. 2011 Oct 22. PMID:22036717 doi:10.1016/j.febslet.2011.10.028

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2y6o"

@@ Line 1: / Line 1: @@
 ==Crystal structure of EphA4 kinase domain in complex with Dasatinib.==
 <StructureSection load='2y6o' size='340' side='right' caption='[[2y6o]], [[Resolution|resolution]] 1.54&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2y6o]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2Y6O OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2Y6O FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2y6o]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2Y6O OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2Y6O FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1N1:N-(2-CHLORO-6-METHYLPHENYL)-2-({6-[4-(2-HYDROXYETHYL)PIPERAZIN-1-YL]-2-METHYLPYRIMIDIN-4-YL}AMINO)-1,3-THIAZOLE-5-CARBOXAMIDE'>1N1</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2y6m|2y6m]], [[2xyu|2xyu]], [[1b0x|1b0x]]</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=2y6o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2y6o OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2y6o RCSB], [http://www.ebi.ac.uk/pdbsum/2y6o 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=2y6o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2y6o OCA], [http://pdbe.org/2y6o PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2y6o RCSB], [http://www.ebi.ac.uk/pdbsum/2y6o PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2y6o ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 18: / Line 19: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 2y6o" style="background-color:#fffaf0;"></div>
 ==See Also==
@@ Line 25: / Line 27: @@
 __TOC__
 </StructureSection>
-[[Category: Mus musculus]]
+[[Category: Lk3 transgenic mice]]
 [[Category: Receptor protein-tyrosine kinase]]
 [[Category: Celie, P H.N]]

2y6o

From Proteopedia

Revision as of 16:36, 5 August 2016

Crystal structure of EphA4 kinase domain in complex with Dasatinib.

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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