View source for 5bms


==Crystal structure of P21-activated kinase 4 in complex with an inhibitor compound 29==
<StructureSection load='5bms' size='340' side='right'caption='[[5bms]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5bms]] 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=5BMS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5BMS 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]] 2.903&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4T6:N~2~-[(7-CHLORO-1H-BENZIMIDAZOL-6-YL)METHYL]-N~4~-(5-CYCLOPROPYL-1H-PYRAZOL-3-YL)PYRIMIDINE-2,4-DIAMINE'>4T6</scene>, <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=5bms FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5bms OCA], [https://pdbe.org/5bms PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5bms RCSB], [https://www.ebi.ac.uk/pdbsum/5bms PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5bms ProSAT]</span></td></tr>
</table>
== Function ==
[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;">
== Publication Abstract from PubMed ==
The p21-activated kinases (PAKs) play important roles in cytoskeletal organization, cellular morphogenesis, and survival and have generated significant attention as potential therapeutic targets for cancer. Following a high-throughput screen, we identified an aminopyrazole scaffold-based series that was optimized to yield group I selective PAK inhibitors. A structure-based design effort aimed at targeting the ribose pocket for both potency and selectivity led to much-improved group I vs II selectivity. Early lead compounds contained a basic primary amine, which was found to be a major metabolic soft spot with in vivo clearance proceeding predominantly via N-acetylation. We succeeded in identifying replacements with improved metabolic stability, leading to compounds with lower in vivo rodent clearance and excellent group I PAK selectivity.

Structure-Guided Design of Group I Selective p21-Activated Kinase Inhibitors.,Crawford JJ, Lee W, Aliagas I, Mathieu S, Hoeflich KP, Zhou W, Wang W, Rouge L, Murray L, La H, Liu N, Fan PW, Cheong J, Heise CE, Ramaswamy S, Mintzer R, Liu Y, Chao Q, Rudolph J J Med Chem. 2015 Jun 25;58(12):5121-36. doi: 10.1021/acs.jmedchem.5b00572. Epub, 2015 Jun 12. PMID:26030457<ref>PMID:26030457</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5bms" style="background-color:#fffaf0;"></div>

==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]]