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5i0b

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Revision as of 08:39, 27 May 2020

Structure of PAK4

Structural highlights

5i0b is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
NonStd Res:
Gene:	PAK4, KIAA1142 (HUMAN)
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

p21-Activated kinases (PAKs) which belong to the family of ste20 serine/threonine protein kinases regulate cytoskeletal reorganization, cell motility, cell proliferation, and oncogenic transformation which are all related to the cellular functions during cancer induction and metastasis. The fact that PAK mutations are detected in multiple tumor tissues makes PAKs a novel therapeutic drug target. In this study, an imidazo[4,5-b]pyridine-based PAK4 inhibitor, KY-04045 (6-Bromo-2-(3-isopropyl-1-methyl-1H-pyrazol-4-yl)-1H-imidazo[4,5-b]pyridine), was discovered using a virtual site-directed fragment-based drug design and was validated using an inhibition assay. Although PAK4 affinity to KY-04045 seems much weaker than that of the reported PAK4 inhibitors, the location of KY-04045 is clearly defined in the structure of PAK4 co-crystallized with KY-04045. The crystal structure illustrates that the pyrazole and imidazopyridine rings of KY-04045 are sufficient for mediating PAK4 hinge loop interaction. Hence, we believe that KY-04045 can be exploited as a basic building block in designing novel imidazo[4,5-b]pyridine-based PAK4 inhibitors.

The discovery and the structural basis of an imidazo[4,5-b]pyridine-based p21-activated kinase 4 inhibitor.,Park JK, Kim S, Han YJ, Kim SH, Kang NS, Lee H, Park S Bioorg Med Chem Lett. 2016 Jun 1;26(11):2580-3. doi: 10.1016/j.bmcl.2016.04.037. , Epub 2016 Apr 16. PMID:27117431^[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
↑ Park JK, Kim S, Han YJ, Kim SH, Kang NS, Lee H, Park S. The discovery and the structural basis of an imidazo[4,5-b]pyridine-based p21-activated kinase 4 inhibitor. Bioorg Med Chem Lett. 2016 Jun 1;26(11):2580-3. doi: 10.1016/j.bmcl.2016.04.037. , Epub 2016 Apr 16. PMID:27117431 doi:http://dx.doi.org/10.1016/j.bmcl.2016.04.037

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/5i0b"

@@ Line 1: / Line 1: @@
 ==Structure of PAK4==
-<StructureSection load='5i0b' size='340' side='right' caption='[[5i0b]], [[Resolution|resolution]] 3.09&Aring;' scene=''>
+<StructureSection load='5i0b' size='340' side='right'caption='[[5i0b]], [[Resolution|resolution]] 3.09&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5i0b]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5I0B OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5I0B FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5i0b]] 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=5I0B OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5I0B FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=67U:6-BROMO-2-[1-METHYL-3-(PROPAN-2-YL)-1H-PYRAZOL-4-YL]-1H-IMIDAZO[4,5-B]PYRIDINE'>67U</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=67U:6-BROMO-2-[1-METHYL-3-(PROPAN-2-YL)-1H-PYRAZOL-4-YL]-1H-IMIDAZO[4,5-B]PYRIDINE'>67U</scene></td></tr>
 <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='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PAK4, KIAA1142 ([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_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=5i0b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5i0b OCA], [http://pdbe.org/5i0b PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5i0b RCSB], [http://www.ebi.ac.uk/pdbsum/5i0b PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5i0b ProSAT]</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=5i0b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5i0b OCA], [http://pdbe.org/5i0b PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5i0b RCSB], [http://www.ebi.ac.uk/pdbsum/5i0b PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5i0b ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 20: / Line 21: @@
 </div>
 <div class="pdbe-citations 5i0b" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Non-specific serine/threonine protein kinase]]
 [[Category: Park, S Y]]
 [[Category: Kinase]]
 [[Category: Transferase-transferase inihibitor complex]]

5i0b

From Proteopedia

Revision as of 08:39, 27 May 2020

Structure of PAK4

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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