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| | ==Crystal Structure of Human Vaccinia-related kinase 2 (VRK-2) bound to BI-D1870== | | ==Crystal Structure of Human Vaccinia-related kinase 2 (VRK-2) bound to BI-D1870== |
| - | <StructureSection load='5uu1' size='340' side='right' caption='[[5uu1]], [[Resolution|resolution]] 2.00Å' scene=''> | + | <StructureSection load='5uu1' size='340' side='right'caption='[[5uu1]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5uu1]] is a 1 chain structure. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=5tkx 5tkx]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UU1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5UU1 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5uu1]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=5tkx 5tkx]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UU1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5UU1 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7DZ:(7S)-2-[(3,5-DIFLUORO-4-HYDROXYPHENYL)AMINO]-5,7-DIMETHYL-8-(3-METHYLBUTYL)-7,8-DIHYDROPTERIDIN-6(5H)-ONE'>7DZ</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]] 2Å</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_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7DZ:(7S)-2-[(3,5-DIFLUORO-4-HYDROXYPHENYL)AMINO]-5,7-DIMETHYL-8-(3-METHYLBUTYL)-7,8-DIHYDROPTERIDIN-6(5H)-ONE'>7DZ</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=5uu1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5uu1 OCA], [http://pdbe.org/5uu1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5uu1 RCSB], [http://www.ebi.ac.uk/pdbsum/5uu1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5uu1 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=5uu1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5uu1 OCA], [https://pdbe.org/5uu1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5uu1 RCSB], [https://www.ebi.ac.uk/pdbsum/5uu1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5uu1 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/VRK2_HUMAN VRK2_HUMAN]] Serine/threonine kinase that regulates several signal transduction pathways. Isoform 1 modulates the stress response to hypoxia and cytokines, such as interleukin-1 beta (IL1B) and this is dependent on its interaction with MAPK8IP1, which assembles mitogen-activated protein kinase (MAPK) complexes. Inhibition of signal transmission mediated by the assembly of MAPK8IP1-MAPK complexes reduces JNK phosphorylation and JUN-dependent transcription. Phosphorylates 'Thr-18' of p53/TP53, histone H3, and may also phosphorylate MAPK8IP1. Phosphorylates BANF1 and disrupts its ability to bind DNA and reduces its binding to LEM domain-containing proteins. Downregulates the transactivation of transcription induced by ERBB2, HRAS, BRAF, and MEK1. Blocks the phosphorylation of ERK in response to ERBB2 and HRAS. Can also phosphorylate the following substrates that are commonly used to establish in vitro kinase activity: casein, MBP and histone H2B, but it is not sure that this is physiologically relevant.<ref>PMID:16704422</ref> <ref>PMID:14645249</ref> <ref>PMID:16495336</ref> <ref>PMID:17709393</ref> <ref>PMID:18617507</ref> <ref>PMID:18286207</ref> <ref>PMID:20679487</ref> Isoform 2 phosphorylates 'Thr-18' of p53/TP53, as well as histone H3. Reduces p53/TP53 ubiquitination by MDM2, promotes p53/TP53 acetylation by EP300 and thereby increases p53/TP53 stability and activity.<ref>PMID:16704422</ref> <ref>PMID:14645249</ref> <ref>PMID:16495336</ref> <ref>PMID:17709393</ref> <ref>PMID:18617507</ref> <ref>PMID:18286207</ref> <ref>PMID:20679487</ref> | + | [https://www.uniprot.org/uniprot/VRK2_HUMAN VRK2_HUMAN] Serine/threonine kinase that regulates several signal transduction pathways. Isoform 1 modulates the stress response to hypoxia and cytokines, such as interleukin-1 beta (IL1B) and this is dependent on its interaction with MAPK8IP1, which assembles mitogen-activated protein kinase (MAPK) complexes. Inhibition of signal transmission mediated by the assembly of MAPK8IP1-MAPK complexes reduces JNK phosphorylation and JUN-dependent transcription. Phosphorylates 'Thr-18' of p53/TP53, histone H3, and may also phosphorylate MAPK8IP1. Phosphorylates BANF1 and disrupts its ability to bind DNA and reduces its binding to LEM domain-containing proteins. Downregulates the transactivation of transcription induced by ERBB2, HRAS, BRAF, and MEK1. Blocks the phosphorylation of ERK in response to ERBB2 and HRAS. Can also phosphorylate the following substrates that are commonly used to establish in vitro kinase activity: casein, MBP and histone H2B, but it is not sure that this is physiologically relevant.<ref>PMID:16704422</ref> <ref>PMID:14645249</ref> <ref>PMID:16495336</ref> <ref>PMID:17709393</ref> <ref>PMID:18617507</ref> <ref>PMID:18286207</ref> <ref>PMID:20679487</ref> Isoform 2 phosphorylates 'Thr-18' of p53/TP53, as well as histone H3. Reduces p53/TP53 ubiquitination by MDM2, promotes p53/TP53 acetylation by EP300 and thereby increases p53/TP53 stability and activity.<ref>PMID:16704422</ref> <ref>PMID:14645249</ref> <ref>PMID:16495336</ref> <ref>PMID:17709393</ref> <ref>PMID:18617507</ref> <ref>PMID:18286207</ref> <ref>PMID:20679487</ref> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | The human genome encodes two active Vaccinia-related protein kinases (VRK), VRK1 and VRK2. These proteins have been implicated in a number of cellular processes and linked to a variety of tumors. However, understanding the cellular role of VRKs and establishing their potential use as targets for therapeutic intervention has been limited by the lack of tool compounds that can specifically modulate the activity of these kinases in cells. Here we identified BI-D1870, a dihydropteridine inhibitor of RSK kinases, as a promising starting point for the development of chemical probes targeting the active VRKs. We solved co-crystal structures of both VRK1 and VRK2 bound to BI-D1870 and of VRK1 bound to two broad-spectrum inhibitors. These structures revealed that both VRKs can adopt a P-loop folded conformation, which is stabilized by different mechanisms on each protein. Based on these structures, we suggest modifications to the dihydropteridine scaffold that can be explored to produce potent and specific inhibitors towards VRK1 and VRK2. |
| | + | |
| | + | Structural characterization of human Vaccinia-Related Kinases (VRK) bound to small-molecule inhibitors identifies different P-loop conformations.,Counago RM, Allerston CK, Savitsky P, Azevedo H, Godoi PH, Wells CI, Mascarello A, de Souza Gama FH, Massirer KB, Zuercher WJ, Guimaraes CRW, Gileadi O Sci Rep. 2017 Aug 8;7(1):7501. doi: 10.1038/s41598-017-07755-y. PMID:28790404<ref>PMID:28790404</ref> |
| | + | |
| | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | + | </div> |
| | + | <div class="pdbe-citations 5uu1" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Non-specific serine/threonine protein kinase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Arruda, P]] | + | [[Category: Large Structures]] |
| - | [[Category: Bountra, C]] | + | [[Category: Arruda P]] |
| - | [[Category: Counago, R M]] | + | [[Category: Bountra C]] |
| - | [[Category: Edwards, A M]] | + | [[Category: Counago RM]] |
| - | [[Category: Gileadi, O]] | + | [[Category: Edwards AM]] |
| - | [[Category: Structural genomic]]
| + | [[Category: Gileadi O]] |
| - | [[Category: Protein kinase domain]]
| + | |
| - | [[Category: Sgc]]
| + | |
| - | [[Category: Transferase]]
| + | |
| - | [[Category: Transferase-transferase inhibitor complex]]
| + | |
| Structural highlights
Function
VRK2_HUMAN Serine/threonine kinase that regulates several signal transduction pathways. Isoform 1 modulates the stress response to hypoxia and cytokines, such as interleukin-1 beta (IL1B) and this is dependent on its interaction with MAPK8IP1, which assembles mitogen-activated protein kinase (MAPK) complexes. Inhibition of signal transmission mediated by the assembly of MAPK8IP1-MAPK complexes reduces JNK phosphorylation and JUN-dependent transcription. Phosphorylates 'Thr-18' of p53/TP53, histone H3, and may also phosphorylate MAPK8IP1. Phosphorylates BANF1 and disrupts its ability to bind DNA and reduces its binding to LEM domain-containing proteins. Downregulates the transactivation of transcription induced by ERBB2, HRAS, BRAF, and MEK1. Blocks the phosphorylation of ERK in response to ERBB2 and HRAS. Can also phosphorylate the following substrates that are commonly used to establish in vitro kinase activity: casein, MBP and histone H2B, but it is not sure that this is physiologically relevant.[1] [2] [3] [4] [5] [6] [7] Isoform 2 phosphorylates 'Thr-18' of p53/TP53, as well as histone H3. Reduces p53/TP53 ubiquitination by MDM2, promotes p53/TP53 acetylation by EP300 and thereby increases p53/TP53 stability and activity.[8] [9] [10] [11] [12] [13] [14]
Publication Abstract from PubMed
The human genome encodes two active Vaccinia-related protein kinases (VRK), VRK1 and VRK2. These proteins have been implicated in a number of cellular processes and linked to a variety of tumors. However, understanding the cellular role of VRKs and establishing their potential use as targets for therapeutic intervention has been limited by the lack of tool compounds that can specifically modulate the activity of these kinases in cells. Here we identified BI-D1870, a dihydropteridine inhibitor of RSK kinases, as a promising starting point for the development of chemical probes targeting the active VRKs. We solved co-crystal structures of both VRK1 and VRK2 bound to BI-D1870 and of VRK1 bound to two broad-spectrum inhibitors. These structures revealed that both VRKs can adopt a P-loop folded conformation, which is stabilized by different mechanisms on each protein. Based on these structures, we suggest modifications to the dihydropteridine scaffold that can be explored to produce potent and specific inhibitors towards VRK1 and VRK2.
Structural characterization of human Vaccinia-Related Kinases (VRK) bound to small-molecule inhibitors identifies different P-loop conformations.,Counago RM, Allerston CK, Savitsky P, Azevedo H, Godoi PH, Wells CI, Mascarello A, de Souza Gama FH, Massirer KB, Zuercher WJ, Guimaraes CRW, Gileadi O Sci Rep. 2017 Aug 8;7(1):7501. doi: 10.1038/s41598-017-07755-y. PMID:28790404[15]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Blanco S, Klimcakova L, Vega FM, Lazo PA. The subcellular localization of vaccinia-related kinase-2 (VRK2) isoforms determines their different effect on p53 stability in tumour cell lines. FEBS J. 2006 Jun;273(11):2487-504. PMID:16704422 doi:http://dx.doi.org/10.1111/j.1742-4658.2006.05256.x
- ↑ Nichols RJ, Traktman P. Characterization of three paralogous members of the Mammalian vaccinia related kinase family. J Biol Chem. 2004 Feb 27;279(9):7934-46. Epub 2003 Nov 25. PMID:14645249 doi:http://dx.doi.org/10.1074/jbc.M310813200
- ↑ Nichols RJ, Wiebe MS, Traktman P. The vaccinia-related kinases phosphorylate the N' terminus of BAF, regulating its interaction with DNA and its retention in the nucleus. Mol Biol Cell. 2006 May;17(5):2451-64. Epub 2006 Feb 22. PMID:16495336 doi:http://dx.doi.org/10.1091/mbc.E05-12-1179
- ↑ Blanco S, Santos C, Lazo PA. Vaccinia-related kinase 2 modulates the stress response to hypoxia mediated by TAK1. Mol Cell Biol. 2007 Oct;27(20):7273-83. Epub 2007 Aug 20. PMID:17709393 doi:http://dx.doi.org/10.1128/MCB.00025-07
- ↑ Sanz-Garcia M, Lopez-Sanchez I, Lazo PA. Proteomics identification of nuclear Ran GTPase as an inhibitor of human VRK1 and VRK2 (vaccinia-related kinase) activities. Mol Cell Proteomics. 2008 Nov;7(11):2199-214. doi: 10.1074/mcp.M700586-MCP200., Epub 2008 Jul 9. PMID:18617507 doi:10.1074/mcp.M700586-MCP200
- ↑ Blanco S, Sanz-Garcia M, Santos CR, Lazo PA. Modulation of interleukin-1 transcriptional response by the interaction between VRK2 and the JIP1 scaffold protein. PLoS One. 2008 Feb 20;3(2):e1660. doi: 10.1371/journal.pone.0001660. PMID:18286207 doi:http://dx.doi.org/10.1371/journal.pone.0001660
- ↑ Fernandez IF, Blanco S, Lozano J, Lazo PA. VRK2 inhibits mitogen-activated protein kinase signaling and inversely correlates with ErbB2 in human breast cancer. Mol Cell Biol. 2010 Oct;30(19):4687-97. doi: 10.1128/MCB.01581-09. Epub 2010 Aug , 2. PMID:20679487 doi:http://dx.doi.org/10.1128/MCB.01581-09
- ↑ Blanco S, Klimcakova L, Vega FM, Lazo PA. The subcellular localization of vaccinia-related kinase-2 (VRK2) isoforms determines their different effect on p53 stability in tumour cell lines. FEBS J. 2006 Jun;273(11):2487-504. PMID:16704422 doi:http://dx.doi.org/10.1111/j.1742-4658.2006.05256.x
- ↑ Nichols RJ, Traktman P. Characterization of three paralogous members of the Mammalian vaccinia related kinase family. J Biol Chem. 2004 Feb 27;279(9):7934-46. Epub 2003 Nov 25. PMID:14645249 doi:http://dx.doi.org/10.1074/jbc.M310813200
- ↑ Nichols RJ, Wiebe MS, Traktman P. The vaccinia-related kinases phosphorylate the N' terminus of BAF, regulating its interaction with DNA and its retention in the nucleus. Mol Biol Cell. 2006 May;17(5):2451-64. Epub 2006 Feb 22. PMID:16495336 doi:http://dx.doi.org/10.1091/mbc.E05-12-1179
- ↑ Blanco S, Santos C, Lazo PA. Vaccinia-related kinase 2 modulates the stress response to hypoxia mediated by TAK1. Mol Cell Biol. 2007 Oct;27(20):7273-83. Epub 2007 Aug 20. PMID:17709393 doi:http://dx.doi.org/10.1128/MCB.00025-07
- ↑ Sanz-Garcia M, Lopez-Sanchez I, Lazo PA. Proteomics identification of nuclear Ran GTPase as an inhibitor of human VRK1 and VRK2 (vaccinia-related kinase) activities. Mol Cell Proteomics. 2008 Nov;7(11):2199-214. doi: 10.1074/mcp.M700586-MCP200., Epub 2008 Jul 9. PMID:18617507 doi:10.1074/mcp.M700586-MCP200
- ↑ Blanco S, Sanz-Garcia M, Santos CR, Lazo PA. Modulation of interleukin-1 transcriptional response by the interaction between VRK2 and the JIP1 scaffold protein. PLoS One. 2008 Feb 20;3(2):e1660. doi: 10.1371/journal.pone.0001660. PMID:18286207 doi:http://dx.doi.org/10.1371/journal.pone.0001660
- ↑ Fernandez IF, Blanco S, Lozano J, Lazo PA. VRK2 inhibits mitogen-activated protein kinase signaling and inversely correlates with ErbB2 in human breast cancer. Mol Cell Biol. 2010 Oct;30(19):4687-97. doi: 10.1128/MCB.01581-09. Epub 2010 Aug , 2. PMID:20679487 doi:http://dx.doi.org/10.1128/MCB.01581-09
- ↑ Counago RM, Allerston CK, Savitsky P, Azevedo H, Godoi PH, Wells CI, Mascarello A, de Souza Gama FH, Massirer KB, Zuercher WJ, Guimaraes CRW, Gileadi O. Structural characterization of human Vaccinia-Related Kinases (VRK) bound to small-molecule inhibitors identifies different P-loop conformations. Sci Rep. 2017 Aug 8;7(1):7501. doi: 10.1038/s41598-017-07755-y. PMID:28790404 doi:http://dx.doi.org/10.1038/s41598-017-07755-y
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