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4two

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Revision as of 01:50, 10 March 2017

Human EphA3 Kinase domain in complex with compound 164

Structural highlights

4two is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Activity:	Receptor protein-tyrosine kinase, with EC number 2.7.10.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[EPHA3_HUMAN] Defects in EPHA3 may be a cause of colorectal cancer (CRC) [MIM:114500].

Function

[EPHA3_HUMAN] Receptor tyrosine kinase which binds promiscuously 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 for ephrin-A ligands it binds preferentially EFNA5. Upon activation by EFNA5 regulates cell-cell adhesion, cytoskeletal organization and cell migration. Plays a role in cardiac cells migration and differentiation and regulates the formation of the atrioventricular canal and septum during development probably through activation by EFNA1. Involved in the retinotectal mapping of neurons. May also control the segregation but not the guidance of motor and sensory axons during neuromuscular circuit development.^[1]

Publication Abstract from PubMed

We have solved the crystal structures of the EphA3 tyrosine kinase in complex with nine small-molecule inhibitors, which represent five different chemotypes and three main binding modes, i.e., types I and I1/2 (DFG in) and type II (DFG out). The three structures with type I1/2 inhibitors show that the higher affinity with respect to type I is due to an additional polar group (hydroxyl or pyrazole ring of indazole) which is fully buried and is involved in the same hydrogen bonds as the (urea or amide) linker of the type II inhibitors. Overall, the type I and type II binding modes belong to the lock-and-key and induced fit mechanism, respectively. In the type II binding, the scaffold in contact with the hinge region influences the position of the Phe765 side chain of the DFG motif and the orientation of the Gly-rich loop. The binding mode of Birb796 in the EphA3 kinase does not involve any hydrogen bond with the hinge region, which is different from the Birb796/p38 MAP kinase complex. Our structural analysis emphasizes the importance of accounting for structural plasticity of the ATP binding site in the design of type II inhibitors of tyrosine kinases.

Structural Analysis of the Binding of Type I, I1/2, and II Inhibitors to Eph Tyrosine Kinases.,Dong J, Zhao H, Zhou T, Spiliotopoulos D, Rajendran C, Li XD, Huang D, Caflisch A ACS Med Chem Lett. 2014 Sep 29;6(1):79-83. doi: 10.1021/ml500355x. eCollection, 2015 Jan 8. PMID:25589935^[2]

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

References

↑ Lawrenson ID, Wimmer-Kleikamp SH, Lock P, Schoenwaelder SM, Down M, Boyd AW, Alewood PF, Lackmann M. Ephrin-A5 induces rounding, blebbing and de-adhesion of EphA3-expressing 293T and melanoma cells by CrkII and Rho-mediated signalling. J Cell Sci. 2002 Mar 1;115(Pt 5):1059-72. PMID:11870224
↑ Dong J, Zhao H, Zhou T, Spiliotopoulos D, Rajendran C, Li XD, Huang D, Caflisch A. Structural Analysis of the Binding of Type I, I1/2, and II Inhibitors to Eph Tyrosine Kinases. ACS Med Chem Lett. 2014 Sep 29;6(1):79-83. doi: 10.1021/ml500355x. eCollection, 2015 Jan 8. PMID:25589935 doi:http://dx.doi.org/10.1021/ml500355x

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4two"

Categories: Receptor protein-tyrosine kinase | Caflisch, A | Dong, J | Transferase | Transferase/transferase inhibitor

@@ Line 1: / Line 1: @@
 ==Human EphA3 Kinase domain in complex with compound 164==
 <StructureSection load='4two' size='340' side='right' caption='[[4two]], [[Resolution|resolution]] 2.05&Aring;' scene=''>
@@ Line 5: / Line 6: @@
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=37W:5-{[3-CARBAMOYL-4-(3,4-DIMETHYLPHENYL)-5-METHYLTHIOPHEN-2-YL]AMINO}-5-OXOPENTANOIC+ACID'>37W</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4two FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4two OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4two RCSB], [http://www.ebi.ac.uk/pdbsum/4two 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=4two FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4two OCA], [http://pdbe.org/4two PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4two RCSB], [http://www.ebi.ac.uk/pdbsum/4two PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4two ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 19: / Line 20: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4two" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

4two

From Proteopedia

Revision as of 01:50, 10 March 2017

Human EphA3 Kinase domain in complex with compound 164

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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