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| | ==PAK6 kinase domain in complex with sunitinib== | | ==PAK6 kinase domain in complex with sunitinib== |
| - | <StructureSection load='4ks8' size='340' side='right' caption='[[4ks8]], [[Resolution|resolution]] 1.95Å' scene=''> | + | <StructureSection load='4ks8' size='340' side='right'caption='[[4ks8]], [[Resolution|resolution]] 1.95Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4ks8]] 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=4KS8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4KS8 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4ks8]] 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=4KS8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4KS8 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=B49:N-[2-(DIETHYLAMINO)ETHYL]-5-[(Z)-(5-FLUORO-2-OXO-1,2-DIHYDRO-3H-INDOL-3-YLIDENE)METHYL]-2,4-DIMETHYL-1H-PYRROLE-3-CARBOXAMIDE'>B49</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=B49:N-[2-(DIETHYLAMINO)ETHYL]-5-[(Z)-(5-FLUORO-2-OXO-1,2-DIHYDRO-3H-INDOL-3-YLIDENE)METHYL]-2,4-DIMETHYL-1H-PYRROLE-3-CARBOXAMIDE'>B49</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4ks8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ks8 OCA], [https://pdbe.org/4ks8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ks8 RCSB], [https://www.ebi.ac.uk/pdbsum/4ks8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ks8 ProSAT]</span></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ks7|4ks7]]</td></tr>
| + | |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PAK6, PAK5 ([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=4ks8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ks8 OCA], [http://pdbe.org/4ks8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ks8 RCSB], [http://www.ebi.ac.uk/pdbsum/4ks8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ks8 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PAK6_HUMAN PAK6_HUMAN]] Serine/threonine protein kinase that plays a role in the regulation of gene transcription. The kinase activity is induced by various effectors including AR or MAP2K6/MAPKK6. Phosphorylates the DNA-binding domain of androgen receptor/AR and thereby inhibits AR-mediated transcription. Inhibits also ESR1-mediated transcription. May play a role in cytoskeleton regulation by interacting with IQGAP1. May protect cells from apoptosis through phosphorylation of BAD.<ref>PMID:14573606</ref> <ref>PMID:20054820</ref> | + | [https://www.uniprot.org/uniprot/PAK6_HUMAN PAK6_HUMAN] Serine/threonine protein kinase that plays a role in the regulation of gene transcription. The kinase activity is induced by various effectors including AR or MAP2K6/MAPKK6. Phosphorylates the DNA-binding domain of androgen receptor/AR and thereby inhibits AR-mediated transcription. Inhibits also ESR1-mediated transcription. May play a role in cytoskeleton regulation by interacting with IQGAP1. May protect cells from apoptosis through phosphorylation of BAD.<ref>PMID:14573606</ref> <ref>PMID:20054820</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Serine/threonine protein kinase|Serine/threonine protein kinase]] | + | *[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Non-specific serine/threonine protein kinase]] | + | [[Category: Large Structures]] |
| - | [[Category: Boggon, T J]] | + | [[Category: Boggon TJ]] |
| - | [[Category: Gao, J]] | + | [[Category: Gao J]] |
| - | [[Category: Phosphorylation]]
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| - | [[Category: Phosphotransfer]]
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| - | [[Category: Protein kinase]]
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| - | [[Category: Transferase-transferase inhibitor complex]]
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| Structural highlights
Function
PAK6_HUMAN Serine/threonine protein kinase that plays a role in the regulation of gene transcription. The kinase activity is induced by various effectors including AR or MAP2K6/MAPKK6. Phosphorylates the DNA-binding domain of androgen receptor/AR and thereby inhibits AR-mediated transcription. Inhibits also ESR1-mediated transcription. May play a role in cytoskeleton regulation by interacting with IQGAP1. May protect cells from apoptosis through phosphorylation of BAD.[1] [2]
Publication Abstract from PubMed
The p21-activated kinases (PAKs) are important effectors of Rho-family small GTPases. The PAK family consists of two groups, type I and type II, which have different modes of regulation and signaling. PAK6, a type II PAK, influences behavior and locomotor function in mice and has an ascribed role in androgen receptor signaling. Here we show that PAK6 has a peptide substrate specificity very similar to the other type II PAKs, PAK4 and PAK5 (PAK7). We find that PAK6 catalytic activity is inhibited by a peptide corresponding to its N-terminal pseudosubstrate. Introduction of a melanoma-associated mutation, P52L, into this peptide reduces pseudosubstrate autoinhibition of PAK6, and increases phosphorylation of its substrate PACSIN1 (Syndapin I) in cells. Finally we determine two co-crystal structures of PAK6 catalytic domain in complex with ATP-competitive inhibitors. We determined the 1.4 A co-crystal structure of PAK6 with the type II PAK inhibitor PF-3758309, and the 1.95 A co-crystal structure of PAK6 with sunitinib. These findings provide new insights into the structure-function relationships of PAK6 and may facilitate development of PAK6 targeted therapies.
Substrate and Inhibitor Specificity of the Type II p21-Activated Kinase, PAK6.,Gao J, Ha BH, Lou HJ, Morse EM, Zhang R, Calderwood DA, Turk BE, Boggon TJ PLoS One. 2013 Oct 28;8(10):e77818. doi: 10.1371/journal.pone.0077818. PMID:24204982[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Schrantz N, da Silva Correia J, Fowler B, Ge Q, Sun Z, Bokoch GM. Mechanism of p21-activated kinase 6-mediated inhibition of androgen receptor signaling. J Biol Chem. 2004 Jan 16;279(3):1922-31. Epub 2003 Oct 22. PMID:14573606 doi:10.1074/jbc.M311145200
- ↑ Zhang M, Siedow M, Saia G, Chakravarti A. Inhibition of p21-activated kinase 6 (PAK6) increases radiosensitivity of prostate cancer cells. Prostate. 2010 Jun 1;70(8):807-16. doi: 10.1002/pros.21114. PMID:20054820 doi:10.1002/pros.21114
- ↑ Gao J, Ha BH, Lou HJ, Morse EM, Zhang R, Calderwood DA, Turk BE, Boggon TJ. Substrate and Inhibitor Specificity of the Type II p21-Activated Kinase, PAK6. PLoS One. 2013 Oct 28;8(10):e77818. doi: 10.1371/journal.pone.0077818. PMID:24204982 doi:http://dx.doi.org/10.1371/journal.pone.0077818
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