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| | <StructureSection load='4two' size='340' side='right'caption='[[4two]], [[Resolution|resolution]] 2.05Å' scene=''> | | <StructureSection load='4two' size='340' side='right'caption='[[4two]], [[Resolution|resolution]] 2.05Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4two]] 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=4TWO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4TWO FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4two]] 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=4TWO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4TWO FirstGlance]. <br> |
| - | </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> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.047Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">EPHA3, ETK, ETK1, HEK, TYRO4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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'>[https://proteopedia.org/fgij/fg.htm?mol=4two FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4two OCA], [https://pdbe.org/4two PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4two RCSB], [https://www.ebi.ac.uk/pdbsum/4two PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4two 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=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> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/EPHA3_HUMAN EPHA3_HUMAN]] Defects in EPHA3 may be a cause of colorectal cancer (CRC) [MIM:[http://omim.org/entry/114500 114500]]. | + | [https://www.uniprot.org/uniprot/EPHA3_HUMAN EPHA3_HUMAN] Defects in EPHA3 may be a cause of colorectal cancer (CRC) [MIM:[https://omim.org/entry/114500 114500]. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/EPHA3_HUMAN 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.<ref>PMID:11870224</ref> | + | [https://www.uniprot.org/uniprot/EPHA3_HUMAN 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.<ref>PMID:11870224</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Ephrin receptor|Ephrin receptor]] | + | *[[Ephrin receptor 3D structures|Ephrin receptor 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Receptor protein-tyrosine kinase]]
| + | [[Category: Caflisch A]] |
| - | [[Category: Caflisch, A]] | + | [[Category: Dong J]] |
| - | [[Category: Dong, J]] | + | |
| - | [[Category: Transferase]]
| + | |
| - | [[Category: Transferase/transferase inhibitor]]
| + | |
| Structural highlights
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.
See Also
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
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