5da3

From Proteopedia

(Difference between revisions)

Revision as of 10:27, 21 June 2023

Crystal structure of PTK6 Kinase domain with inhibitor

Structural highlights

5da3 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PTK6_HUMAN Non-receptor tyrosine-protein kinase implicated in the regulation of a variety of signaling pathways that control the differentiation and maintenance of normal epithelia, as well as tumor growth. Function seems to be context dependent and differ depending on cell type, as well as its intracellular localization. A number of potential nuclear and cytoplasmic substrates have been identified. These include the RNA-binding proteins: KHDRBS1/SAM68, KHDRBS2/SLM1, KHDRBS3/SLM2 and SFPQ/PSF; transcription factors: STAT3 and STAT5A/B and a variety of signaling molecules: ARHGAP35/p190RhoGAP, PXN/paxillin, BTK/ATK, STAP2/BKS. Associates also with a variety of proteins that are likely upstream of PTK6 in various signaling pathways, or for which PTK6 may play an adapter-like role. These proteins include ADAM15, EGFR, ERBB2, ERBB3 and IRS4. In normal or non-tumorigenic tissues, PTK6 promotes cellular differentiation and apoptosis. In tumors PTK6 contributes to cancer progression by sensitizing cells to mitogenic signals and enhancing proliferation, anchorage-independent survival and migration/invasion. Association with EGFR, ERBB2, ERBB3 may contribute to mammary tumor development and growth through enhancement of EGF-induced signaling via BTK/AKT and PI3 kinase. Contributes to migration and proliferation by contributing to EGF-mediated phosphorylation of ARHGAP35/p190RhoGAP, which promotes association with RASA1/p120RasGAP, inactivating RhoA while activating RAS. EGF stimulation resulted in phosphorylation of PNX/Paxillin by PTK6 and activation of RAC1 via CRK/CrKII, thereby promoting migration and invasion. PTK6 activates STAT3 and STAT5B to promote proliferation. Nuclear PTK6 may be important for regulating growth in normal epithelia, while cytoplasmic PTK6 might activate oncogenic signaling pathways.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] Isoform 2 inhibits PTK6 phosphorylation and PTK6 association with other tyrosine-phosphorylated proteins.^[10] ^[11] ^[12] ^[13] ^[14] ^[15] ^[16] ^[17] ^[18]

Publication Abstract from PubMed

Human Protein tyrosine kinase 6 (PTK6)(EC:2.7.10.2), also known as the breast tumor kinase (BRK), is an intracellular non-receptor Src-related tyrosine kinase expressed five-fold or more in human breast tumors and breast cancer cell lines but its expression being low or completely absent from normal mammary gland. There is a recent interest in targeting PTK6-positive breast cancer by developing small molecule inhibitor against PTK6. Novel imidazo[1,2-a]pyrazin-8-amines (IPA) derivative compounds and FDA approved drug, Dasatinib are reported to inhibit PTK6 kinase activity with IC50 in nM range. To understand binding mode of these compounds and key interactions that drive the potency against PTK6, one of the IPA compounds and Dasatinib were chosen to study through X-ray crystallography. The recombinant PTK6 kinase domain was purified and co-crystallized at room temperature by the sitting-drop vapor diffusion method, collected X-ray diffraction data at in-house and resolved co-crystal structure of PTK6-KD with Dasatinib at 2.24 A and with IPA compound at 1.70 A resolution. Both these structures are in DFG-in & alphaC-helix-out conformation with unambiguous electron density for Dasatinib or IPA compound bound at the ATP-binding pocket. Relative difference in potency between Dasatinib and IPA compound is delineated through the additional interactions derived from the occupation of additional pocket by Dasatinib at gatekeeper area. Refined crystallographic coordinates for the kinase domain of PTK6 in complex with IPA compound and Dasatinib have been submitted to Protein Data Bank under the accession number 5DA3 and 5H2U respectively.

Co-crystal structures of PTK6: With Dasatinib at 2.24 A, with novel imidazo[1,2-a]pyrazin-8-amine derivative inhibitor at 1.70 A resolution.,Thakur MK, Birudukota S, Swaminathan S, Battula SK, Vadivelu S, Tyagi R, Gosu R Biochem Biophys Res Commun. 2016 Dec 18. pii: S0006-291X(16)32070-8. doi:, 10.1016/j.bbrc.2016.12.030. PMID:27993680^[19]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Mitchell PJ, Sara EA, Crompton MR. A novel adaptor-like protein which is a substrate for the non-receptor tyrosine kinase, BRK. Oncogene. 2000 Aug 31;19(37):4273-82. PMID:10980601 doi:http://dx.doi.org/10.1038/sj.onc.1203775
↑ Haegebarth A, Heap D, Bie W, Derry JJ, Richard S, Tyner AL. The nuclear tyrosine kinase BRK/Sik phosphorylates and inhibits the RNA-binding activities of the Sam68-like mammalian proteins SLM-1 and SLM-2. J Biol Chem. 2004 Dec 24;279(52):54398-404. Epub 2004 Oct 7. PMID:15471878 doi:http://dx.doi.org/10.1074/jbc.M409579200
↑ Chen HY, Shen CH, Tsai YT, Lin FC, Huang YP, Chen RH. Brk activates rac1 and promotes cell migration and invasion by phosphorylating paxillin. Mol Cell Biol. 2004 Dec;24(24):10558-72. PMID:15572663 doi:http://dx.doi.org/10.1128/MCB.24.24.10558-10572.2004
↑ Zhang P, Ostrander JH, Faivre EJ, Olsen A, Fitzsimmons D, Lange CA. Regulated association of protein kinase B/Akt with breast tumor kinase. J Biol Chem. 2005 Jan 21;280(3):1982-91. Epub 2004 Nov 10. PMID:15539407 doi:http://dx.doi.org/10.1074/jbc.M412038200
↑ Lukong KE, Larocque D, Tyner AL, Richard S. Tyrosine phosphorylation of sam68 by breast tumor kinase regulates intranuclear localization and cell cycle progression. J Biol Chem. 2005 Nov 18;280(46):38639-47. Epub 2005 Sep 22. PMID:16179349 doi:http://dx.doi.org/10.1074/jbc.M505802200
↑ Liu L, Gao Y, Qiu H, Miller WT, Poli V, Reich NC. Identification of STAT3 as a specific substrate of breast tumor kinase. Oncogene. 2006 Aug 10;25(35):4904-12. Epub 2006 Mar 27. PMID:16568091 doi:http://dx.doi.org/10.1038/sj.onc.1209501
↑ Weaver AM, Silva CM. Signal transducer and activator of transcription 5b: a new target of breast tumor kinase/protein tyrosine kinase 6. Breast Cancer Res. 2007;9(6):R79. PMID:17997837 doi:http://dx.doi.org/10.1186/bcr1794
↑ Shen CH, Chen HY, Lin MS, Li FY, Chang CC, Kuo ML, Settleman J, Chen RH. Breast tumor kinase phosphorylates p190RhoGAP to regulate rho and ras and promote breast carcinoma growth, migration, and invasion. Cancer Res. 2008 Oct 1;68(19):7779-87. doi: 10.1158/0008-5472.CAN-08-0997. PMID:18829532 doi:http://dx.doi.org/10.1158/0008-5472.CAN-08-0997
↑ Brauer PM, Zheng Y, Evans MD, Dominguez-Brauer C, Peehl DM, Tyner AL. The alternative splice variant of protein tyrosine kinase 6 negatively regulates growth and enhances PTK6-mediated inhibition of beta-catenin. PLoS One. 2011 Mar 30;6(3):e14789. doi: 10.1371/journal.pone.0014789. PMID:21479203 doi:http://dx.doi.org/10.1371/journal.pone.0014789
↑ Mitchell PJ, Sara EA, Crompton MR. A novel adaptor-like protein which is a substrate for the non-receptor tyrosine kinase, BRK. Oncogene. 2000 Aug 31;19(37):4273-82. PMID:10980601 doi:http://dx.doi.org/10.1038/sj.onc.1203775
↑ Haegebarth A, Heap D, Bie W, Derry JJ, Richard S, Tyner AL. The nuclear tyrosine kinase BRK/Sik phosphorylates and inhibits the RNA-binding activities of the Sam68-like mammalian proteins SLM-1 and SLM-2. J Biol Chem. 2004 Dec 24;279(52):54398-404. Epub 2004 Oct 7. PMID:15471878 doi:http://dx.doi.org/10.1074/jbc.M409579200
↑ Chen HY, Shen CH, Tsai YT, Lin FC, Huang YP, Chen RH. Brk activates rac1 and promotes cell migration and invasion by phosphorylating paxillin. Mol Cell Biol. 2004 Dec;24(24):10558-72. PMID:15572663 doi:http://dx.doi.org/10.1128/MCB.24.24.10558-10572.2004
↑ Zhang P, Ostrander JH, Faivre EJ, Olsen A, Fitzsimmons D, Lange CA. Regulated association of protein kinase B/Akt with breast tumor kinase. J Biol Chem. 2005 Jan 21;280(3):1982-91. Epub 2004 Nov 10. PMID:15539407 doi:http://dx.doi.org/10.1074/jbc.M412038200
↑ Lukong KE, Larocque D, Tyner AL, Richard S. Tyrosine phosphorylation of sam68 by breast tumor kinase regulates intranuclear localization and cell cycle progression. J Biol Chem. 2005 Nov 18;280(46):38639-47. Epub 2005 Sep 22. PMID:16179349 doi:http://dx.doi.org/10.1074/jbc.M505802200
↑ Liu L, Gao Y, Qiu H, Miller WT, Poli V, Reich NC. Identification of STAT3 as a specific substrate of breast tumor kinase. Oncogene. 2006 Aug 10;25(35):4904-12. Epub 2006 Mar 27. PMID:16568091 doi:http://dx.doi.org/10.1038/sj.onc.1209501
↑ Weaver AM, Silva CM. Signal transducer and activator of transcription 5b: a new target of breast tumor kinase/protein tyrosine kinase 6. Breast Cancer Res. 2007;9(6):R79. PMID:17997837 doi:http://dx.doi.org/10.1186/bcr1794
↑ Shen CH, Chen HY, Lin MS, Li FY, Chang CC, Kuo ML, Settleman J, Chen RH. Breast tumor kinase phosphorylates p190RhoGAP to regulate rho and ras and promote breast carcinoma growth, migration, and invasion. Cancer Res. 2008 Oct 1;68(19):7779-87. doi: 10.1158/0008-5472.CAN-08-0997. PMID:18829532 doi:http://dx.doi.org/10.1158/0008-5472.CAN-08-0997
↑ Brauer PM, Zheng Y, Evans MD, Dominguez-Brauer C, Peehl DM, Tyner AL. The alternative splice variant of protein tyrosine kinase 6 negatively regulates growth and enhances PTK6-mediated inhibition of beta-catenin. PLoS One. 2011 Mar 30;6(3):e14789. doi: 10.1371/journal.pone.0014789. PMID:21479203 doi:http://dx.doi.org/10.1371/journal.pone.0014789
↑ Thakur MK, Birudukota S, Swaminathan S, Battula SK, Vadivelu S, Tyagi R, Gosu R. Co-crystal structures of PTK6: With Dasatinib at 2.24 A, with novel imidazo[1,2-a]pyrazin-8-amine derivative inhibitor at 1.70 A resolution. Biochem Biophys Res Commun. 2016 Dec 18. pii: S0006-291X(16)32070-8. doi:, 10.1016/j.bbrc.2016.12.030. PMID:27993680 doi:http://dx.doi.org/10.1016/j.bbrc.2016.12.030

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5da3"

@@ Line 3: / Line 3: @@
 <StructureSection load='5da3' size='340' side='right'caption='[[5da3]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5da3]] 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=5DA3 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5DA3 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5da3]] 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=5DA3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5DA3 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=58V:(2-CHLORO-4-{[6-CYCLOPROPYL-3-(1H-PYRAZOL-4-YL)IMIDAZO[1,2-A]PYRAZIN-8-YL]AMINO}PHENYL)(MORPHOLIN-4-YL)METHANONE'>58V</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=58V:(2-CHLORO-4-{[6-CYCLOPROPYL-3-(1H-PYRAZOL-4-YL)IMIDAZO[1,2-A]PYRAZIN-8-YL]AMINO}PHENYL)(MORPHOLIN-4-YL)METHANONE'>58V</scene>, <scene name='pdbligand=CXM:N-CARBOXYMETHIONINE'>CXM</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
-<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CXM:N-CARBOXYMETHIONINE'>CXM</scene></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=5da3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5da3 OCA], [https://pdbe.org/5da3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5da3 RCSB], [https://www.ebi.ac.uk/pdbsum/5da3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5da3 ProSAT]</span></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PTK6 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </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=5da3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5da3 OCA], [http://pdbe.org/5da3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5da3 RCSB], [http://www.ebi.ac.uk/pdbsum/5da3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5da3 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/PTK6_HUMAN PTK6_HUMAN]] Non-receptor tyrosine-protein kinase implicated in the regulation of a variety of signaling pathways that control the differentiation and maintenance of normal epithelia, as well as tumor growth. Function seems to be context dependent and differ depending on cell type, as well as its intracellular localization. A number of potential nuclear and cytoplasmic substrates have been identified. These include the RNA-binding proteins: KHDRBS1/SAM68, KHDRBS2/SLM1, KHDRBS3/SLM2 and SFPQ/PSF; transcription factors: STAT3 and STAT5A/B and a variety of signaling molecules: ARHGAP35/p190RhoGAP, PXN/paxillin, BTK/ATK, STAP2/BKS. Associates also with a variety of proteins that are likely upstream of PTK6 in various signaling pathways, or for which PTK6 may play an adapter-like role. These proteins include ADAM15, EGFR, ERBB2, ERBB3 and IRS4. In normal or non-tumorigenic tissues, PTK6 promotes cellular differentiation and apoptosis. In tumors PTK6 contributes to cancer progression by sensitizing cells to mitogenic signals and enhancing proliferation, anchorage-independent survival and migration/invasion. Association with EGFR, ERBB2, ERBB3 may contribute to mammary tumor development and growth through enhancement of EGF-induced signaling via BTK/AKT and PI3 kinase. Contributes to migration and proliferation by contributing to EGF-mediated phosphorylation of ARHGAP35/p190RhoGAP, which promotes association with RASA1/p120RasGAP, inactivating RhoA while activating RAS. EGF stimulation resulted in phosphorylation of PNX/Paxillin by PTK6 and activation of RAC1 via CRK/CrKII, thereby promoting migration and invasion. PTK6 activates STAT3 and STAT5B to promote proliferation. Nuclear PTK6 may be important for regulating growth in normal epithelia, while cytoplasmic PTK6 might activate oncogenic signaling pathways.<ref>PMID:10980601</ref> <ref>PMID:15471878</ref> <ref>PMID:15572663</ref> <ref>PMID:15539407</ref> <ref>PMID:16179349</ref> <ref>PMID:16568091</ref> <ref>PMID:17997837</ref> <ref>PMID:18829532</ref> <ref>PMID:21479203</ref>   Isoform 2 inhibits PTK6 phosphorylation and PTK6 association with other tyrosine-phosphorylated proteins.<ref>PMID:10980601</ref> <ref>PMID:15471878</ref> <ref>PMID:15572663</ref> <ref>PMID:15539407</ref> <ref>PMID:16179349</ref> <ref>PMID:16568091</ref> <ref>PMID:17997837</ref> <ref>PMID:18829532</ref> <ref>PMID:21479203</ref>
+[https://www.uniprot.org/uniprot/PTK6_HUMAN PTK6_HUMAN] Non-receptor tyrosine-protein kinase implicated in the regulation of a variety of signaling pathways that control the differentiation and maintenance of normal epithelia, as well as tumor growth. Function seems to be context dependent and differ depending on cell type, as well as its intracellular localization. A number of potential nuclear and cytoplasmic substrates have been identified. These include the RNA-binding proteins: KHDRBS1/SAM68, KHDRBS2/SLM1, KHDRBS3/SLM2 and SFPQ/PSF; transcription factors: STAT3 and STAT5A/B and a variety of signaling molecules: ARHGAP35/p190RhoGAP, PXN/paxillin, BTK/ATK, STAP2/BKS. Associates also with a variety of proteins that are likely upstream of PTK6 in various signaling pathways, or for which PTK6 may play an adapter-like role. These proteins include ADAM15, EGFR, ERBB2, ERBB3 and IRS4. In normal or non-tumorigenic tissues, PTK6 promotes cellular differentiation and apoptosis. In tumors PTK6 contributes to cancer progression by sensitizing cells to mitogenic signals and enhancing proliferation, anchorage-independent survival and migration/invasion. Association with EGFR, ERBB2, ERBB3 may contribute to mammary tumor development and growth through enhancement of EGF-induced signaling via BTK/AKT and PI3 kinase. Contributes to migration and proliferation by contributing to EGF-mediated phosphorylation of ARHGAP35/p190RhoGAP, which promotes association with RASA1/p120RasGAP, inactivating RhoA while activating RAS. EGF stimulation resulted in phosphorylation of PNX/Paxillin by PTK6 and activation of RAC1 via CRK/CrKII, thereby promoting migration and invasion. PTK6 activates STAT3 and STAT5B to promote proliferation. Nuclear PTK6 may be important for regulating growth in normal epithelia, while cytoplasmic PTK6 might activate oncogenic signaling pathways.<ref>PMID:10980601</ref> <ref>PMID:15471878</ref> <ref>PMID:15572663</ref> <ref>PMID:15539407</ref> <ref>PMID:16179349</ref> <ref>PMID:16568091</ref> <ref>PMID:17997837</ref> <ref>PMID:18829532</ref> <ref>PMID:21479203</ref>   Isoform 2 inhibits PTK6 phosphorylation and PTK6 association with other tyrosine-phosphorylated proteins.<ref>PMID:10980601</ref> <ref>PMID:15471878</ref> <ref>PMID:15572663</ref> <ref>PMID:15539407</ref> <ref>PMID:16179349</ref> <ref>PMID:16568091</ref> <ref>PMID:17997837</ref> <ref>PMID:18829532</ref> <ref>PMID:21479203</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 28: / Line 25: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Non-specific protein-tyrosine kinase]]
+[[Category: Battula SK]]
-[[Category: Battula, S K]]
+[[Category: Birudukota S]]
-[[Category: Birudukota, S]]
+[[Category: Gosu R]]
-[[Category: Gosu, R]]
+[[Category: Swaminathan S]]
-[[Category: Swaminathan, S]]
+[[Category: Thakur MK]]
-[[Category: Thakur, M K]]
+[[Category: Tyagi R]]
-[[Category: Tyagi, R]]
+[[Category: Vadivelu S]]
-[[Category: Vadivelu, S]]
-[[Category: Brk]]
-[[Category: Complex]]
-[[Category: Imidazo pyrazin]]
-[[Category: Inhibitor]]
-[[Category: Kinase]]
-[[Category: Ptk6]]
-[[Category: Transferase]]
-[[Category: Transferase-transferase inhibitor complex]]

5da3

From Proteopedia

Revision as of 10:27, 21 June 2023

Crystal structure of PTK6 Kinase domain with inhibitor

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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