6b16
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==P21-activated kinase 1 in complex with a 4-azaindole inhibitor== | |
| + | <StructureSection load='6b16' size='340' side='right'caption='[[6b16]], [[Resolution|resolution]] 2.29Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6b16]] 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=6B16 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6B16 FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.285Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C7Y:N~4~-(5-cyclopropyl-1H-pyrazol-3-yl)-N~2~-[(1S)-1-(1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl]pyrimidine-2,4-diamine'>C7Y</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6b16 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6b16 OCA], [https://pdbe.org/6b16 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6b16 RCSB], [https://www.ebi.ac.uk/pdbsum/6b16 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6b16 ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == 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 == | ||
| + | A series of 4-azaindole-containing p21-activated kinase-1 (PAK1) inhibitors was prepared with the goal of improving physicochemical properties relative to an indole starting point. Indole 1 represented an attractive, non-basic scaffold with good PAK1 affinity and cellular potency but was compromised by high lipophilicity (clogD=4.4). Azaindole 5 was designed as an indole surrogate with the goal of lowering logD and resulted in equipotent PAK1 inhibition with a 2-fold improvement in cellular potency over 1. Structure-activity relationship studies around 5 identified additional 4-azaindole analogs with superior PAK1 biochemical activity (Ki <10nM) and up to 24-fold selectivity for group I over group II PAKs. Compounds from this series showed enhanced permeability, improved aqueous solubility, and lower plasma protein binding over indole 1. The improvement in physicochemical properties translated to a 20-fold decrease in unbound clearance in mouse PK studies for azaindole 5 relative to indole 1. | ||
| - | + | Synthesis and evaluation of a series of 4-azaindole-containing p21-activated kinase-1 inhibitors.,Lee W, Crawford JJ, Aliagas I, Murray LJ, Tay S, Wang W, Heise CE, Hoeflich KP, La H, Mathieu S, Mintzer R, Ramaswamy S, Rouge L, Rudolph J Bioorg Med Chem Lett. 2016 Aug 1;26(15):3518-24. doi: 10.1016/j.bmcl.2016.06.031., Epub 2016 Jun 15. PMID:27346791<ref>PMID:27346791</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: Rouge | + | <div class="pdbe-citations 6b16" style="background-color:#fffaf0;"></div> |
| - | [[Category: Wang | + | |
| + | ==See Also== | ||
| + | *[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Rouge L]] | ||
| + | [[Category: Wang W]] | ||
Current revision
P21-activated kinase 1 in complex with a 4-azaindole inhibitor
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