View source for 8fp1


==PKCeta kinase domain in complex with compound 2==
<StructureSection load='8fp1' size='340' side='right'caption='[[8fp1]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8fp1]] 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=8FP1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8FP1 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]] 1.85&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene>, <scene name='pdbligand=XXF:(3P)-3-[6-chloro-4-(9-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile'>XXF</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=8fp1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8fp1 OCA], [https://pdbe.org/8fp1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8fp1 RCSB], [https://www.ebi.ac.uk/pdbsum/8fp1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8fp1 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/KPCL_HUMAN KPCL_HUMAN] Disease susceptibility is associated with variations affecting the gene represented in this entry.
== Function ==
[https://www.uniprot.org/uniprot/KPCL_HUMAN KPCL_HUMAN] Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that is involved in the regulation of cell differentiation in keratinocytes and pre-B cell receptor, mediates regulation of epithelial tight junction integrity and foam cell formation, and is required for glioblastoma proliferation and apoptosis prevention in MCF-7 cells. In keratinocytes, binds and activates the tyrosine kinase FYN, which in turn blocks epidermal growth factor receptor (EGFR) signaling and leads to keratinocyte growth arrest and differentiation. Associates with the cyclin CCNE1-CDK2-CDKN1B complex and inhibits CDK2 kinase activity, leading to RB1 dephosphorylation and thereby G1 arrest in keratinocytes. In association with RALA activates actin depolymerization, which is necessary for keratinocyte differentiation. In the pre-B cell receptor signaling, functions downstream of BLNK by up-regulating IRF4, which in turn activates L chain gene rearrangement. Regulates epithelial tight junctions (TJs) by phosphorylating occludin (OCLN) on threonine residues, which is necessary for the assembly and maintenance of TJs. In association with PLD2 and via TLR4 signaling, is involved in lipopolysaccharide (LPS)-induced RGS2 down-regulation and foam cell formation. Upon PMA stimulation, mediates glioblastoma cell proliferation by activating the mTOR pathway, the PI3K/AKT pathway and the ERK1-dependent phosphorylation of ELK1. Involved in the protection of glioblastoma cells from irradiation-induced apoptosis by preventing caspase-9 activation. In camptothecin-treated MCF-7 cells, regulates NF-kappa-B upstream signaling by activating IKBKB, and confers protection against DNA damage-induced apoptosis. Promotes oncogenic functions of ATF2 in the nucleus while blocking its apoptotic function at mitochondria. Phosphorylates ATF2 which promotes its nuclear retention and transcriptional activity and negatively regulates its mitochondrial localization.<ref>PMID:11112424</ref> <ref>PMID:10806212</ref> <ref>PMID:11772428</ref> <ref>PMID:15489897</ref> <ref>PMID:17146445</ref> <ref>PMID:18780722</ref> <ref>PMID:19114660</ref> <ref>PMID:20558593</ref> <ref>PMID:21820409</ref> <ref>PMID:22304920</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Immune activating agents represent a valuable class of therapeutics for the treatment of cancer. An area of active research is expanding the types of these therapeutics that are available to patients via targeting new biological mechanisms. Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of immune signaling and a target of high interest for the treatment of cancer. Herein, we present the discovery and optimization of novel amino-6-aryl pyrrolopyrimidine inhibitors of HPK1 starting from hits identified via virtual screening. Key components of this discovery effort were structure-based drug design aided by analyses of normalized B-factors and optimization of lipophilic efficiency.

Design and Synthesis of Functionally Active 5-Amino-6-Aryl Pyrrolopyrimidine Inhibitors of Hematopoietic Progenitor Kinase 1.,Gallego RA, Bernier L, Chen H, Cho-Schultz S, Chung L, Collins M, Del Bel M, Elleraas J, Costa Jones C, Cronin CN, Edwards M, Fang X, Fisher T, He M, Hoffman J, Huo R, Jalaie M, Johnson E, Johnson TW, Kania RS, Kraus M, Lafontaine J, Le P, Liu T, Maestre M, Matthews J, McTigue M, Miller N, Mu Q, Qin X, Ren S, Richardson P, Rohner A, Sach N, Shao L, Smith G, Su R, Sun B, Timofeevski S, Tran P, Wang S, Wang W, Zhou R, Zhu J, Nair SK J Med Chem. 2023 Apr 13;66(7):4888-4909. doi: 10.1021/acs.jmedchem.2c02038. Epub , 2023 Mar 20. PMID:36940470<ref>PMID:36940470</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8fp1" style="background-color:#fffaf0;"></div>

==See Also==
*[[Protein kinase C 3D structures|Protein kinase C 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Johnson E]]