View source for 4otg


==Crystal Structure of PRK1 Catalytic Domain in Complex with Lestaurtinib==
<StructureSection load='4otg' size='340' side='right' caption='[[4otg]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4otg]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OTG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4OTG FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2V9:LESTAURTINIB'>2V9</scene></td></tr>
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4otd|4otd]], [[4oth|4oth]], [[4oti|4oti]]</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Protein_kinase_C Protein kinase C], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.13 2.7.11.13] </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=4otg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4otg OCA], [http://pdbe.org/4otg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4otg RCSB], [http://www.ebi.ac.uk/pdbsum/4otg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4otg ProSAT]</span></td></tr>
</table>
== Function ==
[[http://www.uniprot.org/uniprot/PKN1_HUMAN PKN1_HUMAN]] PKC-related serine/threonine-protein kinase involved in various processes such as regulation of the intermediate filaments of the actin cytoskeleton, cell migration, tumor cell invasion and transcription regulation. Regulates the cytoskeletal network by phosphorylating proteins such as VIM and neurofilament proteins NEFH, NEFL and NEFM, leading to inhibit their polymerization. Phosphorylates 'Ser-575', 'Ser-637' and 'Ser-669' of MAPT/Tau, lowering its ability to bind to microtubules, resulting in disruption of tubulin assembly. Acts as a key coactivator of androgen receptor (ANDR)-dependent transcription, by being recruited to ANDR target genes and specifically mediating phosphorylation of 'Thr-11' of histone H3 (H3T11ph), a specific tag for epigenetic transcriptional activation that promotes demethylation of histone H3 'Lys-9' (H3K9me) by KDM4C/JMJD2C. Phosphorylates HDAC5, HDAC7 and HDAC9, leading to impair their import in the nucleus. Phosphorylates 'Thr-38' of PPP1R14A, 'Ser-159', 'Ser-163' and 'Ser-170' of MARCKS, and GFAP. Able to phosphorylate RPS6 in vitro.<ref>PMID:8557118</ref> <ref>PMID:8621664</ref> <ref>PMID:9175763</ref> <ref>PMID:11104762</ref> <ref>PMID:12514133</ref> <ref>PMID:17332740</ref> <ref>PMID:18066052</ref> <ref>PMID:20188095</ref> <ref>PMID:21754995</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Protein kinase C related kinase 1 (PRK1) is a component of Rho-GTPase, androgen receptor, histone demethylase and histone deacetylase signaling pathways implicated in prostate and ovarian cancer. Herein we describe the crystal structure of PRK1 in apo form, and also in complex with a panel of literature inhibitors including the clinical candidates lestaurtinib and tofacitinib, as well as the staurosporine analog Ro-31-8220. PRK1 is a member of the AGC-kinase class, and as such exhibits the characteristic regulatory sequence at the C-terminus of the catalytic domain - the 'C-tail'. The C-tail fully encircles the catalytic domain placing a phenylalanine in the ATP-binding site. Our inhibitor structures include examples of molecules which both interact with, and displace the C-tail from the active site. This information may assist in the design of inhibitors targeting both PRK and other members of the AGC kinase family.

Crystal Structures of PRK1 in Complex with the Clinical Compounds Lestaurtinib and Tofacitinib Reveal Ligand Induced Conformational Changes.,Chamberlain P, Delker S, Pagarigan B, Mahmoudi A, Jackson P, Abbasian M, Muir J, Raheja N, Cathers B PLoS One. 2014 Aug 11;9(8):e103638. doi: 10.1371/journal.pone.0103638., eCollection 2014. PMID:25111382<ref>PMID:25111382</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4otg" style="background-color:#fffaf0;"></div>

==See Also==
*[[Serine/threonine protein kinase|Serine/threonine protein kinase]]
*[[Student Project 1 for UMass Chemistry 423 Spring 2015|Student Project 1 for UMass Chemistry 423 Spring 2015]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Protein kinase C]]
[[Category: Abbassian, M]]
[[Category: B., Pagarigan]]
[[Category: Cathers, B]]
[[Category: Chamberlain, P P]]
[[Category: Delker, S]]
[[Category: Jackson, P]]
[[Category: Mahmoudi, A]]
[[Category: Muir, J]]
[[Category: Raheja, N]]
[[Category: Atp binding]]
[[Category: Kinase]]
[[Category: Phosphorylation]]
[[Category: Pkn1]]
[[Category: Prk1]]
[[Category: Protein kinase]]
[[Category: Protein kinase c related kinase 1]]
[[Category: Transferase-transferase inhibitor complex]]