4eqc - Revision history

OCA at 15:07, 14 March 2024

2024-03-14T15:07:14Z

←Older revision		Revision as of 15:07, 14 March 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4eqc]] 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=4EQC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4EQC FirstGlance]. <br>		<table><tr><td colspan='2'>[[4eqc]] 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=4EQC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4EQC FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene>, <scene name='pdbligand=XR1:6-[2-CHLORO-4-(1,3-THIAZOL-5-YL)PHENYL]-8-ETHYL-2-{[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]AMINO}PYRIDO[2,3-D]PYRIMIDIN-7(8H)-ONE'>XR1</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]] 2.01Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene>, <scene name='pdbligand=XR1:6-[2-CHLORO-4-(1,3-THIAZOL-5-YL)PHENYL]-8-ETHYL-2-{[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]AMINO}PYRIDO[2,3-D]PYRIMIDIN-7(8H)-ONE'>XR1</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=4eqc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4eqc OCA], [https://pdbe.org/4eqc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4eqc RCSB], [https://www.ebi.ac.uk/pdbsum/4eqc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4eqc 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=4eqc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4eqc OCA], [https://pdbe.org/4eqc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4eqc RCSB], [https://www.ebi.ac.uk/pdbsum/4eqc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4eqc ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/PAK1_HUMAN PAK1_HUMAN] Protein kinase involved in intracellular signaling pathways downstream of integrins and receptor-type kinases that plays an important role in cytoskeleton dynamics, in cell adhesion, migration, proliferation, apoptosis, mitosis, and in vesicle-mediated transport processes. Can directly phosphorylate BAD and protects cells against apoptosis. Activated by interaction with CDC42 and RAC1. Functions as GTPase effector that links the Rho-related GTPases CDC42 and RAC1 to the JNK MAP kinase pathway. Phosphorylates and activates MAP2K1, and thereby mediates activation of downstream MAP kinases. Involved in the reorganization of the actin cytoskeleton, actin stress fibers and of focal adhesion complexes. Phosphorylates the tubulin chaperone TBCB and thereby plays a role in the regulation of microtubule biogenesis and organization of the tubulin cytoskeleton. Plays a role in the regulation of insulin secretion in response to elevated glucose levels. Part of a ternary complex that contains PAK1, DVL1 and MUSK that is important for MUSK-dependent regulation of AChR clustering during the formation of the neuromuscular junction (NMJ). Activity is inhibited in cells undergoing apoptosis, potentially due to binding of CDC2L1 and CDC2L2. Phosphorylates MYL9/MLC2. Phosphorylates RAF1 at 'Ser-338' and 'Ser-339' resulting in: activation of RAF1, stimulation of RAF1 translocation to mitochondria, phosphorylation of BAD by RAF1, and RAF1 binding to BCL2.<ref>PMID:8805275</ref> <ref>PMID:9395435</ref> <ref>PMID:9032240</ref> <ref>PMID:9528787</ref> <ref>PMID:10551809</ref> <ref>PMID:11733498</ref> <ref>PMID:12624090</ref> <ref>PMID:12876277</ref> <ref>PMID:14585966</ref> <ref>PMID:15611088</ref> <ref>PMID:15831477</ref> <ref>PMID:16278681</ref> <ref>PMID:17726028</ref> <ref>PMID:17989089</ref> <ref>PMID:22669945</ref>		[https://www.uniprot.org/uniprot/PAK1_HUMAN PAK1_HUMAN] Protein kinase involved in intracellular signaling pathways downstream of integrins and receptor-type kinases that plays an important role in cytoskeleton dynamics, in cell adhesion, migration, proliferation, apoptosis, mitosis, and in vesicle-mediated transport processes. Can directly phosphorylate BAD and protects cells against apoptosis. Activated by interaction with CDC42 and RAC1. Functions as GTPase effector that links the Rho-related GTPases CDC42 and RAC1 to the JNK MAP kinase pathway. Phosphorylates and activates MAP2K1, and thereby mediates activation of downstream MAP kinases. Involved in the reorganization of the actin cytoskeleton, actin stress fibers and of focal adhesion complexes. Phosphorylates the tubulin chaperone TBCB and thereby plays a role in the regulation of microtubule biogenesis and organization of the tubulin cytoskeleton. Plays a role in the regulation of insulin secretion in response to elevated glucose levels. Part of a ternary complex that contains PAK1, DVL1 and MUSK that is important for MUSK-dependent regulation of AChR clustering during the formation of the neuromuscular junction (NMJ). Activity is inhibited in cells undergoing apoptosis, potentially due to binding of CDC2L1 and CDC2L2. Phosphorylates MYL9/MLC2. Phosphorylates RAF1 at 'Ser-338' and 'Ser-339' resulting in: activation of RAF1, stimulation of RAF1 translocation to mitochondria, phosphorylation of BAD by RAF1, and RAF1 binding to BCL2.<ref>PMID:8805275</ref> <ref>PMID:9395435</ref> <ref>PMID:9032240</ref> <ref>PMID:9528787</ref> <ref>PMID:10551809</ref> <ref>PMID:11733498</ref> <ref>PMID:12624090</ref> <ref>PMID:12876277</ref> <ref>PMID:14585966</ref> <ref>PMID:15611088</ref> <ref>PMID:15831477</ref> <ref>PMID:16278681</ref> <ref>PMID:17726028</ref> <ref>PMID:17989089</ref> <ref>PMID:22669945</ref>
-	<div style="background-color:#fffaf0;">
-	== Publication Abstract from PubMed ==
-	The p21-activated kinases (PAKs) are immediate downstream effectors of the Rac/Cdc42 small G-proteins and implicated in promoting tumorigenesis in various types of cancer including breast and lung carcinomas. Recent studies have established a requirement for the PAKs in the pathogenesis of Neurofibromatosis type 2 (NF2), a dominantly inherited cancer disorder caused by mutations at the NF2 gene locus. Merlin, the protein product of the NF2 gene, has been shown to negatively regulate signaling through the PAKs and the tumor suppressive functions of Merlin are mediated, at least in part, through inhibition of the PAKs. Knockdown of PAK1 and PAK2 expression, through RNAi-based approaches, impairs the proliferation of NF2-null schwannoma cells in culture and inhibits their ability to form tumors in vivo. These data implicate the PAKs as potential therapeutic targets. High-throughput screening of a library of small molecules combined with a structure-activity relationship approach resulted in the identification of FRAX597, a small-molecule pyridopyrimidinone, as a potent inhibitor of the group I PAKs. Crystallographic characterization of the FRAX597/PAK1 complex identifies a phenyl ring that traverses the gatekeeper residue and positions the thiazole in the back cavity of the ATP binding site, a site rarely targeted by kinase inhibitors. FRAX597 inhibits the proliferation of NF2-deficient schwannoma cells in culture and displayed potent anti-tumor activity in vivo, impairing schwannoma development in an orthotopic model of NF2. These studies identify a novel class of orally available ATP-competitive Group I PAK inhibitors with significant potential for the treatment of NF2 and other cancers.
-
-	FRAX597, a Small Molecule Inhibitor of the p21-activated Kinases, Inhibits Tumorigenesis of Neurofibromatosis Type 2 (NF2)-associated Schwannomas.,Licciulli S, Maksimoska J, Zhou C, Troutman S, Kota S, Liu Q, Duron S, Campbell D, Chernoff J, Field J, Marmorstein R, Kissil JL J Biol Chem. 2013 Oct 4;288(40):29105-29114. Epub 2013 Aug 19. PMID:23960073<ref>PMID:23960073</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 4eqc" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==

OCA at 04:09, 7 October 2022

2022-10-07T04:09:04Z

←Older revision		Revision as of 04:09, 7 October 2022
Line 1:		Line 1:

	==Crystal structure of PAK1 kinase domain in complex with FRAX597 inhibitor==		==Crystal structure of PAK1 kinase domain in complex with FRAX597 inhibitor==
-	<StructureSection load='4eqc' size='340' side='right' caption='[[4eqc]], [[Resolution\|resolution]] 2.01Å' scene=''>	+	<StructureSection load='4eqc' size='340' side='right'caption='[[4eqc]], [[Resolution\|resolution]] 2.01Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4eqc]] 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=4EQC OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4EQC FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4eqc]] 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=4EQC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4EQC FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=XR1:6-[2-CHLORO-4-(1,3-THIAZOL-5-YL)PHENYL]-8-ETHYL-2-{[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]AMINO}PYRIDO[2,3-D]PYRIMIDIN-7(8H)-ONE'>XR1</scene~~></td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene>, <scene name='pdbligand=XR1:6-[2-CHLORO-4-(1,3-THIAZOL-5-YL)PHENYL]-8-ETHYL-2-{[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]AMINO}PYRIDO[2,3-D]PYRIMIDIN-7(8H)-ONE'>XR1</scene></td></tr>
-	~~<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</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=4eqc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4eqc OCA], [https://pdbe.org/4eqc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4eqc RCSB], [https://www.ebi.ac.uk/pdbsum/4eqc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4eqc ProSAT]</span></td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PAK1 ([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=4eqc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4eqc OCA], [~~http~~://pdbe.org/4eqc PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4eqc RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4eqc PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4eqc ProSAT]</span></td></tr>	+
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/PAK1_HUMAN PAK1_HUMAN]] Protein kinase involved in intracellular signaling pathways downstream of integrins and receptor-type kinases that plays an important role in cytoskeleton dynamics, in cell adhesion, migration, proliferation, apoptosis, mitosis, and in vesicle-mediated transport processes. Can directly phosphorylate BAD and protects cells against apoptosis. Activated by interaction with CDC42 and RAC1. Functions as GTPase effector that links the Rho-related GTPases CDC42 and RAC1 to the JNK MAP kinase pathway. Phosphorylates and activates MAP2K1, and thereby mediates activation of downstream MAP kinases. Involved in the reorganization of the actin cytoskeleton, actin stress fibers and of focal adhesion complexes. Phosphorylates the tubulin chaperone TBCB and thereby plays a role in the regulation of microtubule biogenesis and organization of the tubulin cytoskeleton. Plays a role in the regulation of insulin secretion in response to elevated glucose levels. Part of a ternary complex that contains PAK1, DVL1 and MUSK that is important for MUSK-dependent regulation of AChR clustering during the formation of the neuromuscular junction (NMJ). Activity is inhibited in cells undergoing apoptosis, potentially due to binding of CDC2L1 and CDC2L2. Phosphorylates MYL9/MLC2. Phosphorylates RAF1 at 'Ser-338' and 'Ser-339' resulting in: activation of RAF1, stimulation of RAF1 translocation to mitochondria, phosphorylation of BAD by RAF1, and RAF1 binding to BCL2.<ref>PMID:8805275</ref> <ref>PMID:9395435</ref> <ref>PMID:9032240</ref> <ref>PMID:9528787</ref> <ref>PMID:10551809</ref> <ref>PMID:11733498</ref> <ref>PMID:12624090</ref> <ref>PMID:12876277</ref> <ref>PMID:14585966</ref> <ref>PMID:15611088</ref> <ref>PMID:15831477</ref> <ref>PMID:16278681</ref> <ref>PMID:17726028</ref> <ref>PMID:17989089</ref> <ref>PMID:22669945</ref>	+	[https://www.uniprot.org/uniprot/PAK1_HUMAN PAK1_HUMAN] Protein kinase involved in intracellular signaling pathways downstream of integrins and receptor-type kinases that plays an important role in cytoskeleton dynamics, in cell adhesion, migration, proliferation, apoptosis, mitosis, and in vesicle-mediated transport processes. Can directly phosphorylate BAD and protects cells against apoptosis. Activated by interaction with CDC42 and RAC1. Functions as GTPase effector that links the Rho-related GTPases CDC42 and RAC1 to the JNK MAP kinase pathway. Phosphorylates and activates MAP2K1, and thereby mediates activation of downstream MAP kinases. Involved in the reorganization of the actin cytoskeleton, actin stress fibers and of focal adhesion complexes. Phosphorylates the tubulin chaperone TBCB and thereby plays a role in the regulation of microtubule biogenesis and organization of the tubulin cytoskeleton. Plays a role in the regulation of insulin secretion in response to elevated glucose levels. Part of a ternary complex that contains PAK1, DVL1 and MUSK that is important for MUSK-dependent regulation of AChR clustering during the formation of the neuromuscular junction (NMJ). Activity is inhibited in cells undergoing apoptosis, potentially due to binding of CDC2L1 and CDC2L2. Phosphorylates MYL9/MLC2. Phosphorylates RAF1 at 'Ser-338' and 'Ser-339' resulting in: activation of RAF1, stimulation of RAF1 translocation to mitochondria, phosphorylation of BAD by RAF1, and RAF1 binding to BCL2.<ref>PMID:8805275</ref> <ref>PMID:9395435</ref> <ref>PMID:9032240</ref> <ref>PMID:9528787</ref> <ref>PMID:10551809</ref> <ref>PMID:11733498</ref> <ref>PMID:12624090</ref> <ref>PMID:12876277</ref> <ref>PMID:14585966</ref> <ref>PMID:15611088</ref> <ref>PMID:15831477</ref> <ref>PMID:16278681</ref> <ref>PMID:17726028</ref> <ref>PMID:17989089</ref> <ref>PMID:22669945</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 23:		Line 20:

	==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: Maksimoska, J]]	+	[[Category: Maksimoska J]]
-	[[Category: Marmorstein, R]]	+	[[Category: Marmorstein R]]
-	~~[[Category: Atp-binding]]~~	+
-	~~[[Category: Phosphorylation]]~~	+
-	~~[[Category: Serine/threonine kinase]]~~	+
-	~~[[Category: Transferase-transferase inhibitor complex~~]]	+

OCA at 19:48, 4 August 2016

2016-08-04T19:48:50Z

←Older revision		Revision as of 19:48, 4 August 2016
Line 1:		Line 1:
		+
	==Crystal structure of PAK1 kinase domain in complex with FRAX597 inhibitor==		==Crystal structure of PAK1 kinase domain in complex with FRAX597 inhibitor==
	<StructureSection load='4eqc' size='340' side='right' caption='[[4eqc]], [[Resolution\|resolution]] 2.01Å' scene=''>		<StructureSection load='4eqc' size='340' side='right' caption='[[4eqc]], [[Resolution\|resolution]] 2.01Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4eqc]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Homo_sapiens Homo sapiens~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EQC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4EQC FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4eqc]] 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=4EQC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4EQC FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=XR1:6-[2-CHLORO-4-(1,3-THIAZOL-5-YL)PHENYL]-8-ETHYL-2-{[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]AMINO}PYRIDO[2,3-D]PYRIMIDIN-7(8H)-ONE'>XR1</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=XR1:6-[2-CHLORO-4-(1,3-THIAZOL-5-YL)PHENYL]-8-ETHYL-2-{[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]AMINO}PYRIDO[2,3-D]PYRIMIDIN-7(8H)-ONE'>XR1</scene></td></tr>
	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>		<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PAK1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 ~~Homo sapiens~~])</td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PAK1 ([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='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=4eqc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4eqc OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4eqc RCSB], [http://www.ebi.ac.uk/pdbsum/4eqc 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=4eqc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4eqc OCA], [http://pdbe.org/4eqc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4eqc RCSB], [http://www.ebi.ac.uk/pdbsum/4eqc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4eqc ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 19:		Line 20:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
		+	<div class="pdbe-citations 4eqc" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
Line 26:		Line 28:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Homo sapiens~~]]	+	[[Category: Human]]
	[[Category: Non-specific serine/threonine protein kinase]]		[[Category: Non-specific serine/threonine protein kinase]]
	[[Category: Maksimoska, J]]		[[Category: Maksimoska, J]]

OCA at 12:33, 25 December 2014

2014-12-25T12:33:37Z

←Older revision		Revision as of 12:33, 25 December 2014
Line 9:		Line 9:
	<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=4eqc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4eqc OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4eqc RCSB], [http://www.ebi.ac.uk/pdbsum/4eqc 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=4eqc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4eqc OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4eqc RCSB], [http://www.ebi.ac.uk/pdbsum/4eqc PDBsum]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/PAK1_HUMAN PAK1_HUMAN]] Protein kinase involved in intracellular signaling pathways downstream of integrins and receptor-type kinases that plays an important role in cytoskeleton dynamics, in cell adhesion, migration, proliferation, apoptosis, mitosis, and in vesicle-mediated transport processes. Can directly phosphorylate BAD and protects cells against apoptosis. Activated by interaction with CDC42 and RAC1. Functions as GTPase effector that links the Rho-related GTPases CDC42 and RAC1 to the JNK MAP kinase pathway. Phosphorylates and activates MAP2K1, and thereby mediates activation of downstream MAP kinases. Involved in the reorganization of the actin cytoskeleton, actin stress fibers and of focal adhesion complexes. Phosphorylates the tubulin chaperone TBCB and thereby plays a role in the regulation of microtubule biogenesis and organization of the tubulin cytoskeleton. Plays a role in the regulation of insulin secretion in response to elevated glucose levels. Part of a ternary complex that contains PAK1, DVL1 and MUSK that is important for MUSK-dependent regulation of AChR clustering during the formation of the neuromuscular junction (NMJ). Activity is inhibited in cells undergoing apoptosis, potentially due to binding of CDC2L1 and CDC2L2. Phosphorylates MYL9/MLC2. Phosphorylates RAF1 at 'Ser-338' and 'Ser-339' resulting in: activation of RAF1, stimulation of RAF1 translocation to mitochondria, phosphorylation of BAD by RAF1, and RAF1 binding to BCL2.<ref>PMID:8805275</ref> <ref>PMID:9395435</ref> <ref>PMID:9032240</ref> <ref>PMID:9528787</ref> <ref>PMID:10551809</ref> <ref>PMID:11733498</ref> <ref>PMID:12624090</ref> <ref>PMID:12876277</ref> <ref>PMID:14585966</ref> <ref>PMID:15611088</ref> <ref>PMID:15831477</ref> <ref>PMID:16278681</ref> <ref>PMID:17726028</ref> <ref>PMID:17989089</ref> <ref>PMID:22669945</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==

OCA at 11:37, 21 December 2014

2014-12-21T11:37:10Z

←Older revision		Revision as of 11:37, 21 December 2014
Line 1:		Line 1:
-	~~{{STRUCTURE_4eqc\| PDB=4eqc \| SCENE= }}~~	+	==Crystal structure of PAK1 kinase domain in complex with FRAX597 inhibitor==
-	===Crystal structure of PAK1 kinase domain in complex with FRAX597 inhibitor===	+	<StructureSection load='4eqc' size='340' side='right' caption='[[4eqc]], [[Resolution\|resolution]] 2.01Å' scene=''>
-	{~~{ABSTRACT_PUBMED_23960073}~~}	+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[4eqc]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EQC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4EQC FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=XR1:6-[2-CHLORO-4-(1,3-THIAZOL-5-YL)PHENYL]-8-ETHYL-2-{[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]AMINO}PYRIDO[2,3-D]PYRIMIDIN-7(8H)-ONE'>XR1</scene></td></tr>
		+	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PAK1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=4eqc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4eqc OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4eqc RCSB], [http://www.ebi.ac.uk/pdbsum/4eqc PDBsum]</span></td></tr>
		+	</table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The p21-activated kinases (PAKs) are immediate downstream effectors of the Rac/Cdc42 small G-proteins and implicated in promoting tumorigenesis in various types of cancer including breast and lung carcinomas. Recent studies have established a requirement for the PAKs in the pathogenesis of Neurofibromatosis type 2 (NF2), a dominantly inherited cancer disorder caused by mutations at the NF2 gene locus. Merlin, the protein product of the NF2 gene, has been shown to negatively regulate signaling through the PAKs and the tumor suppressive functions of Merlin are mediated, at least in part, through inhibition of the PAKs. Knockdown of PAK1 and PAK2 expression, through RNAi-based approaches, impairs the proliferation of NF2-null schwannoma cells in culture and inhibits their ability to form tumors in vivo. These data implicate the PAKs as potential therapeutic targets. High-throughput screening of a library of small molecules combined with a structure-activity relationship approach resulted in the identification of FRAX597, a small-molecule pyridopyrimidinone, as a potent inhibitor of the group I PAKs. Crystallographic characterization of the FRAX597/PAK1 complex identifies a phenyl ring that traverses the gatekeeper residue and positions the thiazole in the back cavity of the ATP binding site, a site rarely targeted by kinase inhibitors. FRAX597 inhibits the proliferation of NF2-deficient schwannoma cells in culture and displayed potent anti-tumor activity in vivo, impairing schwannoma development in an orthotopic model of NF2. These studies identify a novel class of orally available ATP-competitive Group I PAK inhibitors with significant potential for the treatment of NF2 and other cancers.

-	~~==Function==~~	+	FRAX597, a Small Molecule Inhibitor of the p21-activated Kinases, Inhibits Tumorigenesis of Neurofibromatosis Type 2 (NF2)-associated Schwannomas.,Licciulli S, Maksimoska J, Zhou C, Troutman S, Kota S, Liu Q, Duron S, Campbell D, Chernoff J, Field J, Marmorstein R, Kissil JL J Biol Chem. 2013 Oct 4;288(40):29105-29114. Epub 2013 Aug 19. PMID:23960073<ref>PMID:23960073</ref>
-	~~[[http://www.uniprot.org/uniprot/PAK1_HUMAN PAK1_HUMAN]] Protein kinase involved in intracellular signaling pathways downstream~~ of ~~integrins and receptor~~-~~type kinases that plays an important role in cytoskeleton dynamics~~, ~~in cell adhesion~~, ~~migration~~, ~~proliferation~~, ~~apoptosis~~, ~~mitosis~~, and in vesicle-mediated transport processes. Can directly phosphorylate BAD and protects cells against apoptosis. Activated by interaction with CDC42 and RAC1. Functions as GTPase effector that links the Rho-related GTPases CDC42 and RAC1 to the JNK MAP kinase pathway. Phosphorylates and activates MAP2K1, ~~and thereby mediates activation of downstream MAP kinases. Involved in the reorganization of the actin cytoskeleton~~, actin stress fibers and of focal adhesion complexes. Phosphorylates the tubulin chaperone TBCB and thereby plays a role in the regulation of microtubule biogenesis and organization of the tubulin cytoskeleton. Plays a role in the regulation of insulin secretion in response to elevated glucose levels. Part of a ternary complex that contains PAK1, ~~DVL1 and MUSK that is important for MUSK-dependent regulation of AChR clustering during the formation of the neuromuscular junction (NMJ). Activity is inhibited in cells undergoing apoptosis~~, ~~potentially due to binding of CDC2L1 and CDC2L2. Phosphorylates MYL9/MLC2. Phosphorylates RAF1 at 'Ser-338' and 'Ser-339' resulting in: activation of RAF1~~, ~~stimulation of RAF1 translocation to mitochondria~~, ~~phosphorylation of BAD by RAF1~~, ~~and RAF1 binding to BCL2~~.~~<ref>PMID~~:~~8805275</ref> <ref>~~PMID:9395435</ref> <ref>PMID:9032240</ref> <ref>PMID:9528787</ref> <ref>PMID:10551809</ref> <ref>PMID:11733498</ref> <ref>PMID:12624090</ref> <ref>PMID:12876277</ref> <ref>PMID:14585966</ref> <ref>PMID:15611088</ref> <ref>PMID:15831477</ref> <ref>PMID:16278681</ref> <ref>PMID:17726028</ref> <ref>PMID:17989089</ref> <ref>PMID:~~22669945~~</ref>	+

-	~~==About this Structure==~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[4eqc]] is~~ a ~~1 chain structure with sequence from [http://en~~.~~wikipedia~~.~~org/wiki/Homo_sapiens Homo sapiens]~~. ~~Full crystallographic information is available from [http:~~/~~/oca.weizmann.ac.il/oca-bin/ocashort?id=4EQC OCA].~~	+	</div>

-	==~~Reference~~==	+	==See Also==
-	~~<ref group~~=~~"xtra">PMID:023960073</ref>~~<references ~~group="xtra"~~/><~~references~~/>	+	*[[Serine/threonine protein kinase\|Serine/threonine protein kinase]]
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Non-specific serine/threonine protein kinase]]		[[Category: Non-specific serine/threonine protein kinase]]
-	[[Category: Maksimoska, J.]]	+	[[Category: Maksimoska, J]]
-	[[Category: Marmorstein, R.]]	+	[[Category: Marmorstein, R]]
	[[Category: Atp-binding]]		[[Category: Atp-binding]]
	[[Category: Phosphorylation]]		[[Category: Phosphorylation]]
	[[Category: Serine/threonine kinase]]		[[Category: Serine/threonine kinase]]
	[[Category: Transferase-transferase inhibitor complex]]		[[Category: Transferase-transferase inhibitor complex]]

OCA at 04:50, 10 October 2013

2013-10-10T04:50:18Z

←Older revision		Revision as of 04:50, 10 October 2013
Line 1:		Line 1:
	{{STRUCTURE_4eqc\| PDB=4eqc \| SCENE= }}		{{STRUCTURE_4eqc\| PDB=4eqc \| SCENE= }}
	===Crystal structure of PAK1 kinase domain in complex with FRAX597 inhibitor===		===Crystal structure of PAK1 kinase domain in complex with FRAX597 inhibitor===
		+	{{ABSTRACT_PUBMED_23960073}}

	==Function==		==Function==
Line 9:		Line 10:

	==Reference==		==Reference==
-	<references group="xtra"/><references/>	+	<ref group="xtra">PMID:023960073</ref><references group="xtra"/><references/>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Non-specific serine/threonine protein kinase]]		[[Category: Non-specific serine/threonine protein kinase]]

OCA at 07:36, 28 August 2013

2013-08-28T07:36:09Z

←Older revision		Revision as of 07:36, 28 August 2013
Line 1:		Line 1:
-	~~WITHDRAWN: The~~ PDB ~~entry~~ 4EQC ~~was withdrawn~~.	+	{{STRUCTURE_4eqc\| PDB=4eqc \| SCENE= }}
		+	===Crystal structure of PAK1 kinase domain in complex with FRAX597 inhibitor===
		+
		+	==Function==
		+	[[http://www.uniprot.org/uniprot/PAK1_HUMAN PAK1_HUMAN]] Protein kinase involved in intracellular signaling pathways downstream of integrins and receptor-type kinases that plays an important role in cytoskeleton dynamics, in cell adhesion, migration, proliferation, apoptosis, mitosis, and in vesicle-mediated transport processes. Can directly phosphorylate BAD and protects cells against apoptosis. Activated by interaction with CDC42 and RAC1. Functions as GTPase effector that links the Rho-related GTPases CDC42 and RAC1 to the JNK MAP kinase pathway. Phosphorylates and activates MAP2K1, and thereby mediates activation of downstream MAP kinases. Involved in the reorganization of the actin cytoskeleton, actin stress fibers and of focal adhesion complexes. Phosphorylates the tubulin chaperone TBCB and thereby plays a role in the regulation of microtubule biogenesis and organization of the tubulin cytoskeleton. Plays a role in the regulation of insulin secretion in response to elevated glucose levels. Part of a ternary complex that contains PAK1, DVL1 and MUSK that is important for MUSK-dependent regulation of AChR clustering during the formation of the neuromuscular junction (NMJ). Activity is inhibited in cells undergoing apoptosis, potentially due to binding of CDC2L1 and CDC2L2. Phosphorylates MYL9/MLC2. Phosphorylates RAF1 at 'Ser-338' and 'Ser-339' resulting in: activation of RAF1, stimulation of RAF1 translocation to mitochondria, phosphorylation of BAD by RAF1, and RAF1 binding to BCL2.<ref>PMID:8805275</ref> <ref>PMID:9395435</ref> <ref>PMID:9032240</ref> <ref>PMID:9528787</ref> <ref>PMID:10551809</ref> <ref>PMID:11733498</ref> <ref>PMID:12624090</ref> <ref>PMID:12876277</ref> <ref>PMID:14585966</ref> <ref>PMID:15611088</ref> <ref>PMID:15831477</ref> <ref>PMID:16278681</ref> <ref>PMID:17726028</ref> <ref>PMID:17989089</ref> <ref>PMID:22669945</ref>
		+
		+	==About this Structure==
		+	[[4eqc]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EQC OCA].
		+
		+	==Reference==
		+	<references group="xtra"/><references/>
		+	[[Category: Homo sapiens]]
		+	[[Category: Non-specific serine/threonine protein kinase]]
		+	[[Category: Maksimoska, J.]]
		+	[[Category: Marmorstein, R.]]
		+	[[Category: Atp-binding]]
		+	[[Category: Phosphorylation]]
		+	[[Category: Serine/threonine kinase]]
		+	[[Category: Transferase-transferase inhibitor complex]]

OCA at 10:13, 13 March 2013

2013-03-13T10:13:48Z

←Older revision		Revision as of 10:13, 13 March 2013
Line 1:		Line 1:
-	~~'''Unreleased structure'''~~	+	WITHDRAWN: The PDB entry 4EQC was withdrawn.
-		+
-	The entry ~~4eqc is ON HOLD until Paper Publication~~	+
-		+
-	~~Authors: Maksimoska, J~~.~~, Marmorstein, R.~~	+
-		+
-	~~Description: Crystal structure of PAK1 kinase domain in complex with FRAX597 inhibitor~~	+

OCA at 18:57, 2 May 2012

2012-05-02T18:57:00Z

←Older revision		Revision as of 18:57, 2 May 2012
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 4eqc is ON HOLD	+	The entry 4eqc is ON HOLD until Paper Publication

-	Authors: Maksimoska, J. , Marmorstein, R.	+	Authors: Maksimoska, J., Marmorstein, R.

	Description: Crystal structure of PAK1 kinase domain in complex with FRAX597 inhibitor		Description: Crystal structure of PAK1 kinase domain in complex with FRAX597 inhibitor

OCA: Protected "4eqc" [edit=sysop:move=sysop]

2012-04-25T08:57:16Z

Protected "4eqc" [edit=sysop:move=sysop]

←Older revision

Revision as of 08:57, 25 April 2012