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| | ==Structure of the Axl kinase domain in complex with a macrocyclic inhibitor== | | ==Structure of the Axl kinase domain in complex with a macrocyclic inhibitor== |
| - | <StructureSection load='5u6b' size='340' side='right' caption='[[5u6b]], [[Resolution|resolution]] 2.84Å' scene=''> | + | <StructureSection load='5u6b' size='340' side='right'caption='[[5u6b]], [[Resolution|resolution]] 2.84Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5u6b]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5U6B OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5U6B FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5u6b]] is a 4 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=5U6B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5U6B FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7YS:(10R)-7-amino-11-chloro-12-fluoro-1-(2-hydroxyethyl)-3,10,16-trimethyl-16,17-dihydro-1H-8,4-(azeno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecin-15(10H)-one'>7YS</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]] 2.84Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5u6c|5u6c]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7YS:(10R)-7-amino-11-chloro-12-fluoro-1-(2-hydroxyethyl)-3,10,16-trimethyl-16,17-dihydro-1H-8,4-(azeno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecin-15(10H)-one'>7YS</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=5u6b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5u6b OCA], [https://pdbe.org/5u6b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5u6b RCSB], [https://www.ebi.ac.uk/pdbsum/5u6b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5u6b 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=5u6b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5u6b OCA], [http://pdbe.org/5u6b PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5u6b RCSB], [http://www.ebi.ac.uk/pdbsum/5u6b PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5u6b ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/UFO_HUMAN UFO_HUMAN]] Note=AXL and its ligand GAS6 are highly expressed in thyroid carcinoma tissues, and might thus be involved in thyroid tumorigenesis. Overexpression of AXL and its ligand was also detected in many other cancers such as myeloproliferative disorders, prostatic carcinoma cells, or breast cancer. | + | [https://www.uniprot.org/uniprot/UFO_HUMAN UFO_HUMAN] Note=AXL and its ligand GAS6 are highly expressed in thyroid carcinoma tissues, and might thus be involved in thyroid tumorigenesis. Overexpression of AXL and its ligand was also detected in many other cancers such as myeloproliferative disorders, prostatic carcinoma cells, or breast cancer. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/UFO_HUMAN UFO_HUMAN]] Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding growth factor GAS6 and which is thus regulating many physiological processes including cell survival, cell proliferation, migration and differentiation. Ligand binding at the cell surface induces dimerization and autophosphorylation of AXL. Following activation by ligand, ALX binds and induces tyrosine phosphorylation of PI3-kinase subunits PIK3R1, PIK3R2 and PIK3R3; but also GRB2, PLCG1, LCK and PTPN11. Other downstream substrate candidates for AXL are CBL, NCK2, SOCS1 and TENC1. Recruitment of GRB2 and phosphatidylinositol 3 kinase regulatory subunits by AXL leads to the downstream activation of the AKT kinase. GAS6/AXL signaling plays a role in various processes such as endothelial cell survival during acidification by preventing apoptosis, optimal cytokine signaling during human natural killer cell development, hepatic regeneration, gonadotropin-releasing hormone neuron survival and migration, platelet activation, or regulation of thrombotic responses. Plays also an important role in inhibition of Toll-like receptors (TLRs)-mediated innate immune response. In case of filovirus infection, seems to function as a cell entry factor.<ref>PMID:1656220</ref> <ref>PMID:10403904</ref> <ref>PMID:11484958</ref> <ref>PMID:12364394</ref> <ref>PMID:12490074</ref> <ref>PMID:15507525</ref> <ref>PMID:15733062</ref> <ref>PMID:17005688</ref> <ref>PMID:18840707</ref> | + | [https://www.uniprot.org/uniprot/UFO_HUMAN UFO_HUMAN] Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding growth factor GAS6 and which is thus regulating many physiological processes including cell survival, cell proliferation, migration and differentiation. Ligand binding at the cell surface induces dimerization and autophosphorylation of AXL. Following activation by ligand, ALX binds and induces tyrosine phosphorylation of PI3-kinase subunits PIK3R1, PIK3R2 and PIK3R3; but also GRB2, PLCG1, LCK and PTPN11. Other downstream substrate candidates for AXL are CBL, NCK2, SOCS1 and TENC1. Recruitment of GRB2 and phosphatidylinositol 3 kinase regulatory subunits by AXL leads to the downstream activation of the AKT kinase. GAS6/AXL signaling plays a role in various processes such as endothelial cell survival during acidification by preventing apoptosis, optimal cytokine signaling during human natural killer cell development, hepatic regeneration, gonadotropin-releasing hormone neuron survival and migration, platelet activation, or regulation of thrombotic responses. Plays also an important role in inhibition of Toll-like receptors (TLRs)-mediated innate immune response. In case of filovirus infection, seems to function as a cell entry factor.<ref>PMID:1656220</ref> <ref>PMID:10403904</ref> <ref>PMID:11484958</ref> <ref>PMID:12364394</ref> <ref>PMID:12490074</ref> <ref>PMID:15507525</ref> <ref>PMID:15733062</ref> <ref>PMID:17005688</ref> <ref>PMID:18840707</ref> |
| - | <div style="background-color:#fffaf0;">
| + | |
| - | == Publication Abstract from PubMed ==
| + | |
| - | The receptor tyrosine kinase (RTK) family consisting of Tyro3, Axl and Mer (TAM) is one of the most recently identified RTK families. TAM receptors are upregulated postnatally and maintained at high levels in adults. They all play an important role in immunity, but Axl has also been implicated in cancer and therefore is a target in the discovery and development of novel therapeutics. However, of the three members of the TAM family, the Axl kinase domain is the only one that has so far eluded structure determination. To this end, using differential scanning fluorimetry and hydrogen-deuterium exchange mass spectrometry (HDX-MS), we show here that a lower stability and greater dynamic nature of the Axl kinase domain may account for its poor crystallizability. We present the first structural characterization of the Axl kinase domain in complex with a small molecule macrocyclic inhibitor. The Axl crystal structure revealed two distinct conformational states of the enzyme, providing a first glimpse of what an active TAM receptor kinase may look like, and suggesting a potential role for the juxtamembrane region in enzyme activity. We noted that the ATP/inhibitor binding sites of the TAM members closely resemble each other, posing a challenge for the design of a selective inhibitor. We propose that the differences in the conformational dynamics among the TAM family members could potentially be exploited to achieve inhibitor selectivity for targeted receptors.
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| - | | + | |
| - | The Axl Kinase Domain in Complex with a Macrocyclic Inhibitor Offers First Structural Insights into an Active TAM Receptor Kinase.,Gajiwala KS, Grodsky N, Bolanos B, Feng J, Ferre R, Timofeevski S, Xu M, Murray BW, Johnson TW, Stewart A J Biol Chem. 2017 Jul 19. pii: jbc.M116.771485. doi: 10.1074/jbc.M116.771485. PMID:28724631<ref>PMID:28724631</ref>
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| - | | + | |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| - | </div>
| + | |
| - | <div class="pdbe-citations 5u6b" style="background-color:#fffaf0;"></div>
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| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Receptor protein-tyrosine kinase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Gajiwala, K S]] | + | [[Category: Large Structures]] |
| - | [[Category: Grodsky, N]] | + | [[Category: Gajiwala KS]] |
| - | [[Category: Kinase inhibitor complex]] | + | [[Category: Grodsky N]] |
| - | [[Category: Transferase-transferase inhibitor complex]]
| + | |
| Structural highlights
Disease
UFO_HUMAN Note=AXL and its ligand GAS6 are highly expressed in thyroid carcinoma tissues, and might thus be involved in thyroid tumorigenesis. Overexpression of AXL and its ligand was also detected in many other cancers such as myeloproliferative disorders, prostatic carcinoma cells, or breast cancer.
Function
UFO_HUMAN Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding growth factor GAS6 and which is thus regulating many physiological processes including cell survival, cell proliferation, migration and differentiation. Ligand binding at the cell surface induces dimerization and autophosphorylation of AXL. Following activation by ligand, ALX binds and induces tyrosine phosphorylation of PI3-kinase subunits PIK3R1, PIK3R2 and PIK3R3; but also GRB2, PLCG1, LCK and PTPN11. Other downstream substrate candidates for AXL are CBL, NCK2, SOCS1 and TENC1. Recruitment of GRB2 and phosphatidylinositol 3 kinase regulatory subunits by AXL leads to the downstream activation of the AKT kinase. GAS6/AXL signaling plays a role in various processes such as endothelial cell survival during acidification by preventing apoptosis, optimal cytokine signaling during human natural killer cell development, hepatic regeneration, gonadotropin-releasing hormone neuron survival and migration, platelet activation, or regulation of thrombotic responses. Plays also an important role in inhibition of Toll-like receptors (TLRs)-mediated innate immune response. In case of filovirus infection, seems to function as a cell entry factor.[1] [2] [3] [4] [5] [6] [7] [8] [9]
References
- ↑ O'Bryan JP, Frye RA, Cogswell PC, Neubauer A, Kitch B, Prokop C, Espinosa R 3rd, Le Beau MM, Earp HS, Liu ET. axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase. Mol Cell Biol. 1991 Oct;11(10):5016-31. PMID:1656220
- ↑ Jacob AN, Kalapurakal J, Davidson WR, Kandpal G, Dunson N, Prashar Y, Kandpal RP. A receptor tyrosine kinase, UFO/Axl, and other genes isolated by a modified differential display PCR are overexpressed in metastatic prostatic carcinoma cell line DU145. Cancer Detect Prev. 1999;23(4):325-32. PMID:10403904
- ↑ Berclaz G, Altermatt HJ, Rohrbach V, Kieffer I, Dreher E, Andres AC. Estrogen dependent expression of the receptor tyrosine kinase axl in normal and malignant human breast. Ann Oncol. 2001 Jun;12(6):819-24. PMID:11484958
- ↑ D'Arcangelo D, Gaetano C, Capogrossi MC. Acidification prevents endothelial cell apoptosis by Axl activation. Circ Res. 2002 Oct 4;91(7):e4-12. PMID:12364394
- ↑ Ito M, Nakashima M, Nakayama T, Ohtsuru A, Nagayama Y, Takamura N, Demedchik EP, Sekine I, Yamashita S. Expression of receptor-type tyrosine kinase, Axl, and its ligand, Gas6, in pediatric thyroid carcinomas around chernobyl. Thyroid. 2002 Nov;12(11):971-5. PMID:12490074 doi:10.1089/105072502320908303
- ↑ Gallicchio M, Mitola S, Valdembri D, Fantozzi R, Varnum B, Avanzi GC, Bussolino F. Inhibition of vascular endothelial growth factor receptor 2-mediated endothelial cell activation by Axl tyrosine kinase receptor. Blood. 2005 Mar 1;105(5):1970-6. Epub 2004 Oct 26. PMID:15507525 doi:10.1182/blood-2004-04-1469
- ↑ Gould WR, Baxi SM, Schroeder R, Peng YW, Leadley RJ, Peterson JT, Perrin LA. Gas6 receptors Axl, Sky and Mer enhance platelet activation and regulate thrombotic responses. J Thromb Haemost. 2005 Apr;3(4):733-41. Epub 2005 Feb 23. PMID:15733062 doi:10.1111/j.1538-7836.2005.01186.x
- ↑ Shimojima M, Takada A, Ebihara H, Neumann G, Fujioka K, Irimura T, Jones S, Feldmann H, Kawaoka Y. Tyro3 family-mediated cell entry of Ebola and Marburg viruses. J Virol. 2006 Oct;80(20):10109-16. PMID:17005688 doi:80/20/10109
- ↑ Park IK, Giovenzana C, Hughes TL, Yu J, Trotta R, Caligiuri MA. The Axl/Gas6 pathway is required for optimal cytokine signaling during human natural killer cell development. Blood. 2009 Mar 12;113(11):2470-7. doi: 10.1182/blood-2008-05-157073. Epub 2008, Oct 7. PMID:18840707 doi:10.1182/blood-2008-05-157073
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