5kbq
From Proteopedia
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==Pak1 in complex with bis-anilino pyrimidine inhibitor== | ==Pak1 in complex with bis-anilino pyrimidine inhibitor== | ||
| - | <StructureSection load='5kbq' size='340' side='right' caption='[[5kbq]], [[Resolution|resolution]] 2.58Å' scene=''> | + | <StructureSection load='5kbq' size='340' side='right'caption='[[5kbq]], [[Resolution|resolution]] 2.58Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[5kbq]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KBQ OCA]. For a <b>guided tour on the structure components</b> use [ | + | <table><tr><td colspan='2'>[[5kbq]] is a 2 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=5KBQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5KBQ FirstGlance]. <br> |
| - | </td></tr><tr id=' | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.58Å</td></tr> |
| - | <tr id=' | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IPV:[4-METHYL-3-[METHYL-[2-[(3-METHYLSULFONYL-5-MORPHOLIN-4-YL-PHENYL)AMINO]PYRIMIDIN-4-YL]AMINO]PHENYL]METHANOL'>IPV</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5kbq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kbq OCA], [https://pdbe.org/5kbq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5kbq RCSB], [https://www.ebi.ac.uk/pdbsum/5kbq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5kbq 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> |
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Group I p21-activated kinase (PAK) inhibitors are indicated as important in cancer progression, but achieving high kinase selectivity has been challenging. A bis-anilino pyrimidine PAK1 inhibitor was identified and optimized through structure-based drug design to improve PAK1 potency and achieve high kinase selectivity, giving in vitro probe compound AZ13705339 (18). Reduction of lipophilicity to lower clearance afforded AZ13711265 (14) as an in vivo probe compound with oral exposure in mouse. Such probes will allow further investigation of PAK1 biology. | ||
| + | |||
| + | Optimization of Highly Kinase Selective Bis-anilino Pyrimidine PAK1 Inhibitors.,McCoull W, Hennessy EJ, Blades K, Chuaqui C, Dowling JE, Ferguson AD, Goldberg FW, Howe N, Jones CR, Kemmitt PD, Lamont G, Varnes JG, Ward RA, Yang B ACS Med Chem Lett. 2016 Sep 14;7(12):1118-1123. eCollection 2016 Dec 8. PMID:27994749<ref>PMID:27994749</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 5kbq" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| - | [[Category: | + | [[Category: Homo sapiens]] |
| - | [[Category: | + | [[Category: Large Structures]] |
| - | [[Category: | + | [[Category: Ferguson A]] |
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Current revision
Pak1 in complex with bis-anilino pyrimidine inhibitor
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