|
|
| Line 3: |
Line 3: |
| | <StructureSection load='3qup' size='340' side='right'caption='[[3qup]], [[Resolution|resolution]] 1.90Å' scene=''> | | <StructureSection load='3qup' size='340' side='right'caption='[[3qup]], [[Resolution|resolution]] 1.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3qup]] is a 1 chain structure with sequence from [https://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=3QUP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3QUP FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3qup]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QUP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3QUP FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LUN:(5-FLUORO-1H-INDOL-2-YL)[(3R)-1-[(3R)-PIPERIDIN-3-YL]SPIRO[INDOLE-3,3-PYRROLIDIN]-1(2H)-YL]METHANONE'>LUN</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]] 1.9Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Tyro3, Dtk, Rse ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LUN:(5-FLUORO-1H-INDOL-2-YL)[(3R)-1-[(3R)-PIPERIDIN-3-YL]SPIRO[INDOLE-3,3-PYRROLIDIN]-1(2H)-YL]METHANONE'>LUN</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [https://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=3qup FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qup OCA], [https://pdbe.org/3qup PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3qup RCSB], [https://www.ebi.ac.uk/pdbsum/3qup PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3qup 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=3qup FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qup OCA], [https://pdbe.org/3qup PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3qup RCSB], [https://www.ebi.ac.uk/pdbsum/3qup PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3qup ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/TYRO3_MOUSE TYRO3_MOUSE]] Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to several ligands including TULP1 or GAS6. Regulates many physiological processes including cell survival, migration and differentiation. Ligand binding at the cell surface induces dimerization and autophosphorylation of TYRO3 on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with PIK3R1 and thereby enhances PI3-kinase activity. Activates the AKT survival pathway, including nuclear translocation of NF-kappa-B and up-regulation of transcription of NF-kappa-B-regulated genes. TYRO3 signaling plays a role in various processes such as neuron protection from excitotoxic injury, platelet aggregation and cytoskeleton reorganization. Plays also an important role in inhibition of Toll-like receptors (TLRs)-mediated innate immune response by activating STAT1, which selectively induces production of suppressors of cytokine signaling SOCS1 and SOCS3.<ref>PMID:15650770</ref> <ref>PMID:20363878</ref> <ref>PMID:21084607</ref> <ref>PMID:21291561</ref>
| + | [https://www.uniprot.org/uniprot/TYRO3_MOUSE TYRO3_MOUSE] Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to several ligands including TULP1 or GAS6. Regulates many physiological processes including cell survival, migration and differentiation. Ligand binding at the cell surface induces dimerization and autophosphorylation of TYRO3 on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with PIK3R1 and thereby enhances PI3-kinase activity. Activates the AKT survival pathway, including nuclear translocation of NF-kappa-B and up-regulation of transcription of NF-kappa-B-regulated genes. TYRO3 signaling plays a role in various processes such as neuron protection from excitotoxic injury, platelet aggregation and cytoskeleton reorganization. Plays also an important role in inhibition of Toll-like receptors (TLRs)-mediated innate immune response by activating STAT1, which selectively induces production of suppressors of cytokine signaling SOCS1 and SOCS3.<ref>PMID:15650770</ref> <ref>PMID:20363878</ref> <ref>PMID:21084607</ref> <ref>PMID:21291561</ref> |
| - | <div style="background-color:#fffaf0;">
| + | |
| - | == Publication Abstract from PubMed ==
| + | |
| - | We report the discovery of a novel series of spiroindoline-based inhibitors of Sky kinase that bind in the ATP-binding site and exhibit high levels of kinome selectivity through filling the Ala571-subpocket. These inhibitors exhibit moderate oral bioavailability in the rat due to low absorption across the gut wall.
| + | |
| - | | + | |
| - | Novel and selective spiroindoline-based inhibitors of sky kinase.,Powell NA, Kohrt JT, Filipski KJ, Kaufman M, Sheehan D, Edmunds JE, Delaney A, Wang Y, Bourbonais F, Lee DY, Schwende F, Sun F, McConnell P, Catana C, Chen H, Ohren J, Perrin LA Bioorg Med Chem Lett. 2011 Nov 16. PMID:22119469<ref>PMID:22119469</ref>
| + | |
| - | | + | |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 3qup" style="background-color:#fffaf0;"></div>
| + | |
| | == References == | | == References == |
| | <references/> | | <references/> |
| Line 25: |
Line 15: |
| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Lk3 transgenic mice]] | + | [[Category: Mus musculus]] |
| - | [[Category: Receptor protein-tyrosine kinase]]
| + | [[Category: Ohren JF]] |
| - | [[Category: Ohren, J F]] | + | |
| - | [[Category: Cytoplasmic surface]]
| + | |
| - | [[Category: Gas6 ligand]]
| + | |
| - | [[Category: Kinase domain]]
| + | |
| - | [[Category: Phosphotransfer]]
| + | |
| - | [[Category: Protein kinase inhibitor]]
| + | |
| - | [[Category: Receptor tyrosine kinase]]
| + | |
| - | [[Category: Spirocycle]]
| + | |
| - | [[Category: Transferase-transferase inhibitor complex]]
| + | |
| Structural highlights
Function
TYRO3_MOUSE Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to several ligands including TULP1 or GAS6. Regulates many physiological processes including cell survival, migration and differentiation. Ligand binding at the cell surface induces dimerization and autophosphorylation of TYRO3 on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with PIK3R1 and thereby enhances PI3-kinase activity. Activates the AKT survival pathway, including nuclear translocation of NF-kappa-B and up-regulation of transcription of NF-kappa-B-regulated genes. TYRO3 signaling plays a role in various processes such as neuron protection from excitotoxic injury, platelet aggregation and cytoskeleton reorganization. Plays also an important role in inhibition of Toll-like receptors (TLRs)-mediated innate immune response by activating STAT1, which selectively induces production of suppressors of cytokine signaling SOCS1 and SOCS3.[1] [2] [3] [4]
References
- ↑ Angelillo-Scherrer A, Burnier L, Flores N, Savi P, DeMol M, Schaeffer P, Herbert JM, Lemke G, Goff SP, Matsushima GK, Earp HS, Vesin C, Hoylaerts MF, Plaisance S, Collen D, Conway EM, Wehrle-Haller B, Carmeliet P. Role of Gas6 receptors in platelet signaling during thrombus stabilization and implications for antithrombotic therapy. J Clin Invest. 2005 Feb;115(2):237-46. PMID:15650770 doi:http://dx.doi.org/10.1172/JCI22079
- ↑ Sun B, Qi N, Shang T, Wu H, Deng T, Han D. Sertoli cell-initiated testicular innate immune response through toll-like receptor-3 activation is negatively regulated by Tyro3, Axl, and mer receptors. Endocrinology. 2010 Jun;151(6):2886-97. doi: 10.1210/en.2009-1498. Epub 2010 Apr , 2. PMID:20363878 doi:http://dx.doi.org/10.1210/en.2009-1498
- ↑ Zhong Z, Wang Y, Guo H, Sagare A, Fernandez JA, Bell RD, Barrett TM, Griffin JH, Freeman RS, Zlokovic BV. Protein S protects neurons from excitotoxic injury by activating the TAM receptor Tyro3-phosphatidylinositol 3-kinase-Akt pathway through its sex hormone-binding globulin-like region. J Neurosci. 2010 Nov 17;30(46):15521-34. doi: 10.1523/JNEUROSCI.4437-10.2010. PMID:21084607 doi:http://dx.doi.org/10.1523/JNEUROSCI.4437-10.2010
- ↑ Guo H, Barrett TM, Zhong Z, Fernandez JA, Griffin JH, Freeman RS, Zlokovic BV. Protein S blocks the extrinsic apoptotic cascade in tissue plasminogen activator/N-methyl D-aspartate-treated neurons via Tyro3-Akt-FKHRL1 signaling pathway. Mol Neurodegener. 2011 Feb 3;6:13. doi: 10.1186/1750-1326-6-13. PMID:21291561 doi:http://dx.doi.org/10.1186/1750-1326-6-13
|
