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| | ==Kinase domain of human EphB1, G703C mutant, covalently bound to a quinazoline-based inhibitor== | | ==Kinase domain of human EphB1, G703C mutant, covalently bound to a quinazoline-based inhibitor== |
| - | <StructureSection load='5mjb' size='340' side='right' caption='[[5mjb]], [[Resolution|resolution]] 2.23Å' scene=''> | + | <StructureSection load='5mjb' size='340' side='right'caption='[[5mjb]], [[Resolution|resolution]] 2.23Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5mjb]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MJB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5MJB FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5mjb]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MJB OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5MJB FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7O3:2-CHLORANYL-~{N}-[4-[(2-CHLORANYL-5-OXIDANYL-PHENYL)AMINO]QUINAZOLIN-7-YL]ETHANAMIDE'>7O3</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7O3:2-CHLORANYL-~{N}-[4-[(2-CHLORANYL-5-OXIDANYL-PHENYL)AMINO]QUINAZOLIN-7-YL]ETHANAMIDE'>7O3</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr> | | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</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='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=5mjb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mjb OCA], [http://pdbe.org/5mjb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mjb RCSB], [http://www.ebi.ac.uk/pdbsum/5mjb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mjb ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5mjb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mjb OCA], [http://pdbe.org/5mjb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mjb RCSB], [http://www.ebi.ac.uk/pdbsum/5mjb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mjb ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5mjb" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5mjb" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Ephrin receptor 3D structures|Ephrin receptor 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | + | [[Category: Large Structures]] |
| | [[Category: Receptor protein-tyrosine kinase]] | | [[Category: Receptor protein-tyrosine kinase]] |
| | [[Category: Chen, Y C]] | | [[Category: Chen, Y C]] |
| Structural highlights
Function
[EPHB1_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. Cognate/functional ephrin ligands for this receptor include EFNB1, EFNB2 and EFNB3. During nervous system development, regulates retinal axon guidance redirecting ipsilaterally ventrotemporal retinal ganglion cells axons at the optic chiasm midline. This probably requires repulsive interaction with EFNB2. In the adult nervous system together with EFNB3, regulates chemotaxis, proliferation and polarity of the hippocampus neural progenitors. Beside its role in axon guidance plays also an important redundant role with other ephrin-B receptors in development and maturation of dendritic spines and synapse formation. May also regulate angiogenesis. More generally, may play a role in targeted cell migration and adhesion. Upon activation by EFNB1 and probably other ephrin-B ligands activates the MAPK/ERK and the JNK signaling cascades to regulate cell migration and adhesion respectively.[1] [2] [3] [4] [5]
Publication Abstract from PubMed
Although a previously developed bump-hole approach has proven powerful in generating specific inhibitors for mapping functions of protein kinases, its application is limited by the intolerance of the large-to-small mutation by certain kinases and the inability to control two kinases separately in the same cells. Herein, we describe the development of an alternative chemical-genetic approach to overcome these limitations. Our approach features the use of an engineered cysteine residue at a particular position as a reactive feature to sensitize a kinase of interest to selective covalent blockade by electrophilic inhibitors and is thus termed the Ele-Cys approach. We successfully applied the Ele-Cys approach to identify selective covalent inhibitors of a receptor tyrosine kinase EphB1 and solved cocrystal structures to determine the mode of covalent binding. Importantly, the Ele-Cys and bump-hole approaches afforded orthogonal inhibition of two distinct kinases in the cell, opening the door to their combined use in the study of multikinase signaling pathways.
A Chemical-Genetic Approach to Generate Selective Covalent Inhibitors of Protein Kinases.,Kung A, Schimpl M, Ekanayake A, Chen YC, Overman R, Zhang C ACS Chem Biol. 2017 May 8. doi: 10.1021/acschembio.6b01083. PMID:28459525[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Stein E, Huynh-Do U, Lane AA, Cerretti DP, Daniel TO. Nck recruitment to Eph receptor, EphB1/ELK, couples ligand activation to c-Jun kinase. J Biol Chem. 1998 Jan 16;273(3):1303-8. PMID:9430661
- ↑ Stein E, Lane AA, Cerretti DP, Schoecklmann HO, Schroff AD, Van Etten RL, Daniel TO. Eph receptors discriminate specific ligand oligomers to determine alternative signaling complexes, attachment, and assembly responses. Genes Dev. 1998 Mar 1;12(5):667-78. PMID:9499402
- ↑ Han DC, Shen TL, Miao H, Wang B, Guan JL. EphB1 associates with Grb7 and regulates cell migration. J Biol Chem. 2002 Nov 22;277(47):45655-61. Epub 2002 Sep 9. PMID:12223469 doi:10.1074/jbc.M203165200
- ↑ Vindis C, Cerretti DP, Daniel TO, Huynh-Do U. EphB1 recruits c-Src and p52Shc to activate MAPK/ERK and promote chemotaxis. J Cell Biol. 2003 Aug 18;162(4):661-71. PMID:12925710 doi:http://dx.doi.org/10.1083/jcb.200302073
- ↑ Fasen K, Cerretti DP, Huynh-Do U. Ligand binding induces Cbl-dependent EphB1 receptor degradation through the lysosomal pathway. Traffic. 2008 Feb;9(2):251-66. Epub 2007 Dec 19. PMID:18034775 doi:http://dx.doi.org/10.1111/j.1600-0854.2007.00679.x
- ↑ Kung A, Schimpl M, Ekanayake A, Chen YC, Overman R, Zhang C. A Chemical-Genetic Approach to Generate Selective Covalent Inhibitors of Protein Kinases. ACS Chem Biol. 2017 May 8. doi: 10.1021/acschembio.6b01083. PMID:28459525 doi:http://dx.doi.org/10.1021/acschembio.6b01083
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