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==Crystal Structure of the Human p21-Activated Kinase 4 in Complex with (S)-N-(5-(3-benzyl-1-methylpiperazine-4-carbonyl)-6,6-dimethyl-1,4,5, 6-tetrahydropyrrolo(3,4-c)pyrazol-3-yl)-3-phenoxybenzamide== | ==Crystal Structure of the Human p21-Activated Kinase 4 in Complex with (S)-N-(5-(3-benzyl-1-methylpiperazine-4-carbonyl)-6,6-dimethyl-1,4,5, 6-tetrahydropyrrolo(3,4-c)pyrazol-3-yl)-3-phenoxybenzamide== | ||
<StructureSection load='4app' size='340' side='right' caption='[[4app]], [[Resolution|resolution]] 2.20Å' scene=''> | <StructureSection load='4app' size='340' side='right'caption='[[4app]], [[Resolution|resolution]] 2.20Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4app]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[4app]] 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=4APP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4APP FirstGlance]. <br> | ||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=N53:N-[6,6-DIMETHYL-5-[(2S)-4-METHYL-2-(PHENYLMETHYL)PIPERAZIN-1-YL]CARBONYL-2,4-DIHYDROPYRROLO[3,4-C]PYRAZOL-3-YL]-3-PHENOXY-BENZAMIDE'>N53</scene> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=N53:N-[6,6-DIMETHYL-5-[(2S)-4-METHYL-2-(PHENYLMETHYL)PIPERAZIN-1-YL]CARBONYL-2,4-DIHYDROPYRROLO[3,4-C]PYRAZOL-3-YL]-3-PHENOXY-BENZAMIDE'>N53</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></td></tr> | |||
<tr | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4app FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4app OCA], [https://pdbe.org/4app PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4app RCSB], [https://www.ebi.ac.uk/pdbsum/4app PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4app ProSAT]</span></td></tr> | ||
</table> | |||
== Function == | |||
<table> | [https://www.uniprot.org/uniprot/PAK4_HUMAN 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.<ref>PMID:11278822</ref> <ref>PMID:11313478</ref> <ref>PMID:14560027</ref> <ref>PMID:15660133</ref> <ref>PMID:20507994</ref> <ref>PMID:20805321</ref> <ref>PMID:20631255</ref> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 15: | Line 16: | ||
Discovery of Pyrroloaminopyrazoles as Novel PAK Inhibitors.,Guo C, McAlpine I, Zhang J, Knighton DD, Kephart S, Johnson MC, Li H, Bouzida D, Yang A, Dong L, Marakovits J, Tikhe J, Richardson P, Guo LC, Kania R, Edwards MP, Kraynov E, Christensen J, Piraino J, Lee J, Dagostino E, Del-Carmen C, Deng YL, Smeal T, Murray BW J Med Chem. 2012 May 24;55(10):4728-39. Epub 2012 May 14. PMID:22554206<ref>PMID:22554206</ref> | Discovery of Pyrroloaminopyrazoles as Novel PAK Inhibitors.,Guo C, McAlpine I, Zhang J, Knighton DD, Kephart S, Johnson MC, Li H, Bouzida D, Yang A, Dong L, Marakovits J, Tikhe J, Richardson P, Guo LC, Kania R, Edwards MP, Kraynov E, Christensen J, Piraino J, Lee J, Dagostino E, Del-Carmen C, Deng YL, Smeal T, Murray BW J Med Chem. 2012 May 24;55(10):4728-39. Epub 2012 May 14. PMID:22554206<ref>PMID:22554206</ref> | ||
From | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 4app" style="background-color:#fffaf0;"></div> | |||
==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/> | ||
| Line 25: | Line 27: | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Bouzida | [[Category: Bouzida D]] | ||
[[Category: Christensen | [[Category: Christensen J]] | ||
[[Category: Dagostino | [[Category: Dagostino E]] | ||
[[Category: Del-Carmen | [[Category: Del-Carmen C]] | ||
[[Category: Deng | [[Category: Deng YL]] | ||
[[Category: Dong | [[Category: Dong L]] | ||
[[Category: Edwards | [[Category: Edwards MP]] | ||
[[Category: Guo | [[Category: Guo C]] | ||
[[Category: Guo | [[Category: Guo LC]] | ||
[[Category: Johnson | [[Category: Johnson MC]] | ||
[[Category: Kania | [[Category: Kania R]] | ||
[[Category: Kephart | [[Category: Kephart S]] | ||
[[Category: Knighton | [[Category: Knighton DD]] | ||
[[Category: Kraynov | [[Category: Kraynov E]] | ||
[[Category: Lee | [[Category: Lee J]] | ||
[[Category: Li | [[Category: Li H]] | ||
[[Category: Marakovits | [[Category: Marakovits J]] | ||
[[Category: | [[Category: McAlpine I]] | ||
[[Category: Murray | [[Category: Murray BW]] | ||
[[Category: Piraino | [[Category: Piraino J]] | ||
[[Category: Richardson | [[Category: Richardson P]] | ||
[[Category: Smeal | [[Category: Smeal T]] | ||
[[Category: Tikhe | [[Category: Tikhe J]] | ||
[[Category: Wang | [[Category: Wang C]] | ||
[[Category: Yang | [[Category: Yang A]] | ||
[[Category: Zhang | [[Category: Zhang J]] | ||
Latest revision as of 11:17, 23 October 2024
Crystal Structure of the Human p21-Activated Kinase 4 in Complex with (S)-N-(5-(3-benzyl-1-methylpiperazine-4-carbonyl)-6,6-dimethyl-1,4,5, 6-tetrahydropyrrolo(3,4-c)pyrazol-3-yl)-3-phenoxybenzamideCrystal Structure of the Human p21-Activated Kinase 4 in Complex with (S)-N-(5-(3-benzyl-1-methylpiperazine-4-carbonyl)-6,6-dimethyl-1,4,5, 6-tetrahydropyrrolo(3,4-c)pyrazol-3-yl)-3-phenoxybenzamide
Structural highlights
FunctionPAK4_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 PubMedThe P21-activated kinases (PAK) are emerging antitumor therapeutic targets. In this paper, we describe the discovery of potent PAK inhibitors guided by structure-based drug design. In addition, the efflux of the pyrrolopyrazole series was effectively reduced by applying multiple medicinal chemistry strategies, leading to a series of PAK inhibitors that are orally active in inhibiting tumor growth in vivo. Discovery of Pyrroloaminopyrazoles as Novel PAK Inhibitors.,Guo C, McAlpine I, Zhang J, Knighton DD, Kephart S, Johnson MC, Li H, Bouzida D, Yang A, Dong L, Marakovits J, Tikhe J, Richardson P, Guo LC, Kania R, Edwards MP, Kraynov E, Christensen J, Piraino J, Lee J, Dagostino E, Del-Carmen C, Deng YL, Smeal T, Murray BW J Med Chem. 2012 May 24;55(10):4728-39. Epub 2012 May 14. PMID:22554206[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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