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5myv

From Proteopedia

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Crystal structure of SRPK2 in complex with compound 1

Structural highlights

5myv is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.9Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

SRPK2_HUMAN Serine/arginine-rich protein-specific kinase which specifically phosphorylates its substrates at serine residues located in regions rich in arginine/serine dipeptides, known as RS domains and is involved in the phosphorylation of SR splicing factors and the regulation of splicing. Promotes neuronal apoptosis by up-regulating cyclin-D1 (CCND1) expression. This is done by the phosphorylation of SRSF2, leading to the suppression of p53/TP53 phosphorylation thereby relieving the repressive effect of p53/TP53 on cyclin-D1 (CCND1) expression. Phosphorylates ACIN1, and redistributes it from the nuclear speckles to the nucleoplasm, resulting in cyclin A1 but not cyclin A2 up-regulation. Plays an essential role in spliceosomal B complex formation via the phosphorylation of DDX23/PRP28. Can mediate hepatitis B virus (HBV) core protein phosphorylation. Plays a negative role in the regulation of HBV replication through a mechanism not involving the phosphorylation of the core protein but by reducing the packaging efficiency of the pregenomic RNA (pgRNA) without affecting the formation of the viral core particles.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8]

Publication Abstract from PubMed

Serine/arginine-protein kinase 1 (SRPK1) regulates alternative splicing of VEGF-A to pro-angiogenic isoforms and SRPK1 inhibition can restore the balance of pro/antiangiogenic isoforms to normal physiological levels. The lack of potency and selectivity of available compounds has limited development of SRPK1 inhibitors, with the control of alternative splicing by splicing factor-specific kinases yet to be translated. We present here compounds that occupy a binding pocket created by the unique helical insert of SRPK1, and trigger a backbone flip in the hinge region, that results in potent (<10 nM) and selective inhibition of SRPK1 kinase activity. Treatment with these inhibitors inhibited SRPK1 activity and phosphorylation of serine/arginine splicing factor 1 (SRSF1), resulting in alternative splicing of VEGF-A from pro-angiogenic to antiangiogenic isoforms. This property resulted in potent inhibition of blood vessel growth in models of choroidal angiogenesis in vivo. This work identifies tool compounds for splice isoform selective targeting of pro-angiogenic VEGF, which may lead to new therapeutic strategies for a diversity of diseases where dysfunctional splicing drives disease development.

Development of Potent, Selective SRPK1 Inhibitors as Potential Topical Therapeutics for Neovascular Eye Disease.,Batson J, Toop HD, Redondo C, Babaei-Jadidi R, Chaikuad A, Wearmouth SF, Gibbons B, Allen C, Tallant C, Zhang J, Du C, Hancox JC, Hawtrey T, Da Rocha J, Griffith R, Knapp S, Bates DO, Morris JC ACS Chem Biol. 2017 Mar 17;12(3):825-832. doi: 10.1021/acschembio.6b01048. Epub, 2017 Feb 6. PMID:28135068^[9]

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

References

↑ Daub H, Blencke S, Habenberger P, Kurtenbach A, Dennenmoser J, Wissing J, Ullrich A, Cotten M. Identification of SRPK1 and SRPK2 as the major cellular protein kinases phosphorylating hepatitis B virus core protein. J Virol. 2002 Aug;76(16):8124-37. PMID:12134018
↑ Zheng Y, Fu XD, Ou JH. Suppression of hepatitis B virus replication by SRPK1 and SRPK2 via a pathway independent of the phosphorylation of the viral core protein. Virology. 2005 Nov 10;342(1):150-8. Epub 2005 Aug 24. PMID:16122776 doi:http://dx.doi.org/10.1016/j.virol.2005.07.030
↑ Mathew R, Hartmuth K, Mohlmann S, Urlaub H, Ficner R, Luhrmann R. Phosphorylation of human PRP28 by SRPK2 is required for integration of the U4/U6-U5 tri-snRNP into the spliceosome. Nat Struct Mol Biol. 2008 May;15(5):435-43. doi: 10.1038/nsmb.1415. Epub 2008 Apr, 20. PMID:18425142 doi:http://dx.doi.org/10.1038/nsmb.1415
↑ Jang SW, Yang SJ, Ehlen A, Dong S, Khoury H, Chen J, Persson JL, Ye K. Serine/arginine protein-specific kinase 2 promotes leukemia cell proliferation by phosphorylating acinus and regulating cyclin A1. Cancer Res. 2008 Jun 15;68(12):4559-70. doi: 10.1158/0008-5472.CAN-08-0021. PMID:18559500 doi:http://dx.doi.org/10.1158/0008-5472.CAN-08-0021
↑ Jang SW, Liu X, Fu H, Rees H, Yepes M, Levey A, Ye K. Interaction of Akt-phosphorylated SRPK2 with 14-3-3 mediates cell cycle and cell death in neurons. J Biol Chem. 2009 Sep 4;284(36):24512-25. doi: 10.1074/jbc.M109.026237. Epub 2009, Jul 10. PMID:19592491 doi:10.1074/jbc.M109.026237
↑ Hong Y, Jang SW, Ye K. The N-terminal fragment from caspase-cleaved serine/arginine protein-specific kinase2 (SRPK2) translocates into the nucleus and promotes apoptosis. J Biol Chem. 2011 Jan 7;286(1):777-86. doi: 10.1074/jbc.M110.193441. Epub 2010, Nov 5. PMID:21056976 doi:http://dx.doi.org/10.1074/jbc.M110.193441
↑ Edmond V, Moysan E, Khochbin S, Matthias P, Brambilla C, Brambilla E, Gazzeri S, Eymin B. Acetylation and phosphorylation of SRSF2 control cell fate decision in response to cisplatin. EMBO J. 2011 Feb 2;30(3):510-23. doi: 10.1038/emboj.2010.333. Epub 2010 Dec 14. PMID:21157427 doi:http://dx.doi.org/10.1038/emboj.2010.333
↑ Wang HY, Lin W, Dyck JA, Yeakley JM, Songyang Z, Cantley LC, Fu XD. SRPK2: a differentially expressed SR protein-specific kinase involved in mediating the interaction and localization of pre-mRNA splicing factors in mammalian cells. J Cell Biol. 1998 Feb 23;140(4):737-50. PMID:9472028
↑ Batson J, Toop HD, Redondo C, Babaei-Jadidi R, Chaikuad A, Wearmouth SF, Gibbons B, Allen C, Tallant C, Zhang J, Du C, Hancox JC, Hawtrey T, Da Rocha J, Griffith R, Knapp S, Bates DO, Morris JC. Development of Potent, Selective SRPK1 Inhibitors as Potential Topical Therapeutics for Neovascular Eye Disease. ACS Chem Biol. 2017 Mar 17;12(3):825-832. doi: 10.1021/acschembio.6b01048. Epub, 2017 Feb 6. PMID:28135068 doi:http://dx.doi.org/10.1021/acschembio.6b01048

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

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

@@ Line 3: / Line 3: @@
 <StructureSection load='5myv' size='340' side='right'caption='[[5myv]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5myv]] is a 4 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=5MYV OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5MYV FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5myv]] 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=5MYV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5MYV FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=W4A:5-METHYL-~{N}-[2-(4-METHYLPIPERAZIN-1-YL)-5-(TRIFLUOROMETHYL)PHENYL]FURAN-2-CARBOXAMIDE'>W4A</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]] 2.9&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SRPK2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=W4A:5-METHYL-~{N}-[2-(4-METHYLPIPERAZIN-1-YL)-5-(TRIFLUOROMETHYL)PHENYL]FURAN-2-CARBOXAMIDE'>W4A</scene></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=5myv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5myv OCA], [http://pdbe.org/5myv PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5myv RCSB], [http://www.ebi.ac.uk/pdbsum/5myv PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5myv 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=5myv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5myv OCA], [https://pdbe.org/5myv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5myv RCSB], [https://www.ebi.ac.uk/pdbsum/5myv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5myv ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/SRPK2_HUMAN SRPK2_HUMAN]] Serine/arginine-rich protein-specific kinase which specifically phosphorylates its substrates at serine residues located in regions rich in arginine/serine dipeptides, known as RS domains and is involved in the phosphorylation of SR splicing factors and the regulation of splicing. Promotes neuronal apoptosis by up-regulating cyclin-D1 (CCND1) expression. This is done by the phosphorylation of SRSF2, leading to the suppression of p53/TP53 phosphorylation thereby relieving the repressive effect of p53/TP53 on cyclin-D1 (CCND1) expression. Phosphorylates ACIN1, and redistributes it from the nuclear speckles to the nucleoplasm, resulting in cyclin A1 but not cyclin A2 up-regulation. Plays an essential role in spliceosomal B complex formation via the phosphorylation of DDX23/PRP28. Can mediate hepatitis B virus (HBV) core protein phosphorylation. Plays a negative role in the regulation of HBV replication through a mechanism not involving the phosphorylation of the core protein but by reducing the packaging efficiency of the pregenomic RNA (pgRNA) without affecting the formation of the viral core particles.<ref>PMID:12134018</ref> <ref>PMID:16122776</ref> <ref>PMID:18425142</ref> <ref>PMID:18559500</ref> <ref>PMID:19592491</ref> <ref>PMID:21056976</ref> <ref>PMID:21157427</ref> <ref>PMID:9472028</ref>
+[https://www.uniprot.org/uniprot/SRPK2_HUMAN SRPK2_HUMAN] Serine/arginine-rich protein-specific kinase which specifically phosphorylates its substrates at serine residues located in regions rich in arginine/serine dipeptides, known as RS domains and is involved in the phosphorylation of SR splicing factors and the regulation of splicing. Promotes neuronal apoptosis by up-regulating cyclin-D1 (CCND1) expression. This is done by the phosphorylation of SRSF2, leading to the suppression of p53/TP53 phosphorylation thereby relieving the repressive effect of p53/TP53 on cyclin-D1 (CCND1) expression. Phosphorylates ACIN1, and redistributes it from the nuclear speckles to the nucleoplasm, resulting in cyclin A1 but not cyclin A2 up-regulation. Plays an essential role in spliceosomal B complex formation via the phosphorylation of DDX23/PRP28. Can mediate hepatitis B virus (HBV) core protein phosphorylation. Plays a negative role in the regulation of HBV replication through a mechanism not involving the phosphorylation of the core protein but by reducing the packaging efficiency of the pregenomic RNA (pgRNA) without affecting the formation of the viral core particles.<ref>PMID:12134018</ref> <ref>PMID:16122776</ref> <ref>PMID:18425142</ref> <ref>PMID:18559500</ref> <ref>PMID:19592491</ref> <ref>PMID:21056976</ref> <ref>PMID:21157427</ref> <ref>PMID:9472028</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 23: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Arrowsmith, C H]]
+[[Category: Arrowsmith CH]]
-[[Category: Bountra, C]]
+[[Category: Bountra C]]
-[[Category: Chaikuad, A]]
+[[Category: Chaikuad A]]
-[[Category: Delft, F von]]
+[[Category: Edwards AM]]
-[[Category: Edwards, A M]]
+[[Category: Knapp S]]
-[[Category: Knapp, S]]
+[[Category: Pike ACW]]
-[[Category: Pike, A C.W]]
+[[Category: Savitsky P]]
-[[Category: Structural genomic]]
+[[Category: Von Delft F]]
-[[Category: Savitsky, P]]
-[[Category: Inhibitor]]
-[[Category: Kinase]]
-[[Category: Sgc]]
-[[Category: Splicing kinase]]
-[[Category: Transferase]]

5myv

From Proteopedia

Current revision

Crystal structure of SRPK2 in complex with compound 1

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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