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4njd

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Revision as of 14:44, 4 August 2016

Structure of p21-activated kinase 4 with a novel inhibitor KY-04031

Structural highlights

4njd is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
NonStd Res:
Activity:	Non-specific serine/threonine protein kinase, with EC number 2.7.11.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[PAK4_HUMAN] Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell migration, growth, proliferation or cell survival. Activation by various effectors including growth factor receptors or active CDC42 and RAC1 results in a conformational change and a subsequent autophosphorylation on several serine and/or threonine residues. Phosphorylates and inactivates the protein phosphatase SSH1, leading to increased inhibitory phosphorylation of the actin binding/depolymerizing factor cofilin. Decreased cofilin activity may lead to stabilization of actin filaments. Phosphorylates LIMK1, a kinase that also inhibits the activity of cofilin. Phosphorylates integrin beta5/ITGB5 and thus regulates cell motility. Phosphorylates ARHGEF2 and activates the downstream target RHOA that plays a role in the regulation of assembly of focal adhesions and actin stress fibers. Stimulates cell survival by phosphorylating the BCL2 antagonist of cell death BAD. Alternatively, inhibits apoptosis by preventing caspase-8 binding to death domain receptors in a kinase independent manner. Plays a role in cell-cycle progression by controlling levels of the cell-cycle regulatory protein CDKN1A and by phosphorylating RAN.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7]

Publication Abstract from PubMed

Functional versatility and elevated expression in cancers have endowed p21-activated kinase 4 (PAK4) as one of the first-in-class anti-cancer drug target. In this study, a novel PAK4 inhibitor, KY-04031 (N2-(2-(1H-indol-3-yl)ethyl)-N4-(1H-indazol-5-yl)-6-methoxy-1,3,5-triazine-2,4-di amine), was discovered using a high-throughput screening. Analysis of the complex crystal structure illustrated that both indole and indazole of KY-04031 are responsible for PAK4 hinge interaction. Moreover, the molecule's triazine core was found to mimic the ribose of the natural ATP substrate. The cell-based anti-cancer potency of KY-04031 was less effective than the pyrroloaminopyrazoles; however, the unique molecular feature of KY-04031 can be exploited in designing new PAK4 inhibitors.

Discovery and the structural basis of a novel p21-activated kinase 4 inhibitor.,Ryu BJ, Kim S, Min B, Kim KY, Lee JS, Park WJ, Lee H, Kim SH, Park S Cancer Lett. 2014 Apr 1. pii: S0304-3835(14)00193-1. doi:, 10.1016/j.canlet.2014.03.024. PMID:24704155^[8]

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

References

↑ Gnesutta N, Qu J, Minden A. The serine/threonine kinase PAK4 prevents caspase activation and protects cells from apoptosis. J Biol Chem. 2001 Apr 27;276(17):14414-9. Epub 2001 Jan 24. PMID:11278822 doi:10.1074/jbc.M011046200
↑ Qu J, Cammarano MS, Shi Q, Ha KC, de Lanerolle P, Minden A. Activated PAK4 regulates cell adhesion and anchorage-independent growth. Mol Cell Biol. 2001 May;21(10):3523-33. PMID:11313478 doi:10.1128/MCB.21.10.3523-3533.2001
↑ Gnesutta N, Minden A. Death receptor-induced activation of initiator caspase 8 is antagonized by serine/threonine kinase PAK4. Mol Cell Biol. 2003 Nov;23(21):7838-48. PMID:14560027
↑ Soosairajah J, Maiti S, Wiggan O, Sarmiere P, Moussi N, Sarcevic B, Sampath R, Bamburg JR, Bernard O. Interplay between components of a novel LIM kinase-slingshot phosphatase complex regulates cofilin. EMBO J. 2005 Feb 9;24(3):473-86. Epub 2005 Jan 20. PMID:15660133 doi:7600543
↑ Li Z, Zhang H, Lundin L, Thullberg M, Liu Y, Wang Y, Claesson-Welsh L, Stromblad S. p21-activated kinase 4 phosphorylation of integrin beta5 Ser-759 and Ser-762 regulates cell migration. J Biol Chem. 2010 Jul 30;285(31):23699-710. doi: 10.1074/jbc.M110.123497. Epub, 2010 May 27. PMID:20507994 doi:10.1074/jbc.M110.123497
↑ Bompard G, Rabeharivelo G, Frank M, Cau J, Delsert C, Morin N. Subgroup II PAK-mediated phosphorylation regulates Ran activity during mitosis. J Cell Biol. 2010 Sep 6;190(5):807-22. doi: 10.1083/jcb.200912056. Epub 2010 Aug , 30. PMID:20805321 doi:10.1083/jcb.200912056
↑ Wallace SW, Durgan J, Jin D, Hall A. Cdc42 regulates apical junction formation in human bronchial epithelial cells through PAK4 and Par6B. Mol Biol Cell. 2010 Sep 1;21(17):2996-3006. doi: 10.1091/mbc.E10-05-0429. Epub, 2010 Jul 14. PMID:20631255 doi:10.1091/mbc.E10-05-0429
↑ Ryu BJ, Kim S, Min B, Kim KY, Lee JS, Park WJ, Lee H, Kim SH, Park S. Discovery and the structural basis of a novel p21-activated kinase 4 inhibitor. Cancer Lett. 2014 Apr 1. pii: S0304-3835(14)00193-1. doi:, 10.1016/j.canlet.2014.03.024. PMID:24704155 doi:http://dx.doi.org/10.1016/j.canlet.2014.03.024

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/4njd"

Categories: Non-specific serine/threonine protein kinase | Park, S | Kinase | Transferase-transferase inhibitor complex

@@ Line 1: / Line 1: @@
 ==Structure of p21-activated kinase 4 with a novel inhibitor KY-04031==
 <StructureSection load='4njd' size='340' side='right' caption='[[4njd]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
@@ Line 6: / Line 7: @@
 <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></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='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=4njd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4njd OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4njd RCSB], [http://www.ebi.ac.uk/pdbsum/4njd PDBsum]</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=4njd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4njd OCA], [http://pdbe.org/4njd PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4njd RCSB], [http://www.ebi.ac.uk/pdbsum/4njd PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4njd ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 18: / Line 19: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4njd" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Serine/threonine protein kinase|Serine/threonine protein kinase]]
 == References ==
 <references/>

4njd

From Proteopedia

Revision as of 14:44, 4 August 2016

Structure of p21-activated kinase 4 with a novel inhibitor KY-04031

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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