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| | ==Human EphA3 Kinase domain in complex with quinoxaline derivatives== | | ==Human EphA3 Kinase domain in complex with quinoxaline derivatives== |
| - | <StructureSection load='4p5q' size='340' side='right' caption='[[4p5q]], [[Resolution|resolution]] 1.35Å' scene=''> | + | <StructureSection load='4p5q' size='340' side='right'caption='[[4p5q]], [[Resolution|resolution]] 1.35Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4p5q]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4P5Q OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4P5Q FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4p5q]] 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=4P5Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4P5Q FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=Q0B:2-AMINO-1-(2-CHLOROPHENYL)-N-(3-ETHOXYPROPYL)-1H-PYRROLO[2,3-B]QUINOXALINE-3-CARBOXAMIDE'>Q0B</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]] 1.35Å</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=Q0B:2-AMINO-1-(2-CHLOROPHENYL)-N-(3-ETHOXYPROPYL)-1H-PYRROLO[2,3-B]QUINOXALINE-3-CARBOXAMIDE'>Q0B</scene></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=4p5q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4p5q OCA], [http://pdbe.org/4p5q PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4p5q RCSB], [http://www.ebi.ac.uk/pdbsum/4p5q PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4p5q ProSAT]</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=4p5q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4p5q OCA], [https://pdbe.org/4p5q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4p5q RCSB], [https://www.ebi.ac.uk/pdbsum/4p5q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4p5q 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: Receptor protein-tyrosine kinase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Caflisch, A]] | + | [[Category: Large Structures]] |
| - | [[Category: Dong, J]] | + | [[Category: Caflisch A]] |
| - | [[Category: Transferase]] | + | [[Category: Dong J]] |
| - | [[Category: 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
The X-ray crystal structures of the catalytic domain of the EphA3 tyrosine kinase in complex with two type I inhibitors previously discovered in silico (compounds A and B) were used to design type I1/2 and II inhibitors. Chemical synthesis of about 25 derivatives culminated in the discovery of compounds 11d (type I1/2), 7b, and 7g (both of type II), which have low-nanomolar affinity for Eph kinases in vitro and a good selectivity profile on a panel of 453 human kinases (395 nonmutant). Surface plasmon resonance measurements show a very slow unbinding rate (1/115 min) for inhibitor 7m. Slow dissociation is consistent with a type II binding mode in which the hydrophobic moiety (trifluoromethyl-benzene) of the inhibitor is deeply buried in a cavity originating from the displacement of the Phe side chain of the so-called DFG motif as observed in the crystal structure of compound 7m. The inhibitor 11d displayed good in vivo efficacy in a human breast cancer xenograft.
Pyrrolo[3,2-b]quinoxaline Derivatives as Types I and II Eph Tyrosine Kinase Inhibitors: Structure-Based Design, Synthesis, and in Vivo Validation.,Unzue A, Dong J, Lafleur K, Zhao H, Frugier E, Caflisch A, Nevado C J Med Chem. 2014 Jul 30. PMID:25076195[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
- ↑ Unzue A, Dong J, Lafleur K, Zhao H, Frugier E, Caflisch A, Nevado C. Pyrrolo[3,2-b]quinoxaline Derivatives as Types I and II Eph Tyrosine Kinase Inhibitors: Structure-Based Design, Synthesis, and in Vivo Validation. J Med Chem. 2014 Jul 30. PMID:25076195 doi:http://dx.doi.org/10.1021/jm5009242
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