View source for 3et7


==Crystal structure of PYK2 complexed with PF-2318841==
<StructureSection load='3et7' size='340' side='right'caption='[[3et7]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3et7]] 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=3ET7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3ET7 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]] 2.7&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=349:5-{[4-{[2-(PYRROLIDIN-1-YLSULFONYL)BENZYL]AMINO}-5-(TRIFLUOROMETHYL)PYRIMIDIN-2-YL]AMINO}-1,3-DIHYDRO-2H-INDOL-2-ONE'>349</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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=3et7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3et7 OCA], [https://pdbe.org/3et7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3et7 RCSB], [https://www.ebi.ac.uk/pdbsum/3et7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3et7 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/FAK2_HUMAN FAK2_HUMAN] Note=Aberrant PTK2B/PYK2 expression may play a role in cancer cell proliferation, migration and invasion, in tumor formation and metastasis. Elevated PTK2B/PYK2 expression is seen in gliomas, hepatocellular carcinoma, lung cancer and breast cancer.<ref>PMID:18339875</ref> <ref>PMID:18765415</ref> <ref>PMID:19648005</ref> <ref>PMID:21533080</ref> <ref>PMID:20001213</ref> <ref>PMID:19428251</ref> <ref>PMID:19244237</ref> 
== Function ==
[https://www.uniprot.org/uniprot/FAK2_HUMAN FAK2_HUMAN] Non-receptor protein-tyrosine kinase that regulates reorganization of the actin cytoskeleton, cell polarization, cell migration, adhesion, spreading and bone remodeling. Plays a role in the regulation of the humoral immune response, and is required for normal levels of marginal B-cells in the spleen and normal migration of splenic B-cells. Required for normal macrophage polarization and migration towards sites of inflammation. Regulates cytoskeleton rearrangement and cell spreading in T-cells, and contributes to the regulation of T-cell responses. Promotes osteoclastic bone resorption; this requires both PTK2B/PYK2 and SRC. May inhibit differentiation and activity of osteoprogenitor cells. Functions in signaling downstream of integrin and collagen receptors, immune receptors, G-protein coupled receptors (GPCR), cytokine, chemokine and growth factor receptors, and mediates responses to cellular stress. Forms multisubunit signaling complexes with SRC and SRC family members upon activation; this leads to the phosphorylation of additional tyrosine residues, creating binding sites for scaffold proteins, effectors and substrates. Regulates numerous signaling pathways. Promotes activation of phosphatidylinositol 3-kinase and of the AKT1 signaling cascade. Promotes activation of NOS3. Regulates production of the cellular messenger cGMP. Promotes activation of the MAP kinase signaling cascade, including activation of MAPK1/ERK2, MAPK3/ERK1 and MAPK8/JNK1. Promotes activation of Rho family GTPases, such as RHOA and RAC1. Recruits the ubiquitin ligase MDM2 to P53/TP53 in the nucleus, and thereby regulates P53/TP53 activity, P53/TP53 ubiquitination and proteasomal degradation. Acts as a scaffold, binding to both PDPK1 and SRC, thereby allowing SRC to phosphorylate PDPK1 at 'Tyr-9, 'Tyr-373', and 'Tyr-376'. Promotes phosphorylation of NMDA receptors by SRC family members, and thereby contributes to the regulation of NMDA receptor ion channel activity and intracellular Ca(2+) levels. May also regulate potassium ion transport by phosphorylation of potassium channel subunits. Phosphorylates SRC; this increases SRC kinase activity. Phosphorylates ASAP1, NPHP1, KCNA2 and SHC1. Promotes phosphorylation of ASAP2, RHOU and PXN; this requires both SRC and PTK2/PYK2.<ref>PMID:7544443</ref> <ref>PMID:8849729</ref> <ref>PMID:8670418</ref> <ref>PMID:10022920</ref> <ref>PMID:12771146</ref> <ref>PMID:12893833</ref> <ref>PMID:14585963</ref> <ref>PMID:15050747</ref> <ref>PMID:15166227</ref> <ref>PMID:17634955</ref> <ref>PMID:18339875</ref> <ref>PMID:18765415</ref> <ref>PMID:18086875</ref> <ref>PMID:18587400</ref> <ref>PMID:19207108</ref> <ref>PMID:19648005</ref> <ref>PMID:19086031</ref> <ref>PMID:20521079</ref> <ref>PMID:19880522</ref> <ref>PMID:20381867</ref> <ref>PMID:21357692</ref> <ref>PMID:21533080</ref> <ref>PMID:20001213</ref> <ref>PMID:19428251</ref> <ref>PMID:19244237</ref> 
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/et/3et7_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3et7 ConSurf].
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== Publication Abstract from PubMed ==
The synthesis and SAR for a series of diaminopyrimidines as PYK2 inhibitors are described. Using a combination of library and traditional medicinal chemistry techniques, a FAK-selective chemical series was transformed into compounds possessing good PYK2 potency and 10- to 20-fold selectivity against FAK. Subsequent studies found that the majority of the compounds were positive in a reactive metabolite assay, an indicator for potential toxicological liabilities. Based on the proposed mechanism for bioactivation, as well as a combination of structure-based drug design and traditional medicinal chemistry techniques, a follow-up series of PYK2 inhibitors was identified that maintained PYK2 potency, FAK selectivity and HLM stability, yet were negative in the RM assay.

Trifluoromethylpyrimidine-based inhibitors of proline-rich tyrosine kinase 2 (PYK2): structure-activity relationships and strategies for the elimination of reactive metabolite formation.,Walker DP, Bi FC, Kalgutkar AS, Bauman JN, Zhao SX, Soglia JR, Aspnes GE, Kung DW, Klug-McLeod J, Zawistoski MP, McGlynn MA, Oliver R, Dunn M, Li JC, Richter DT, Cooper BA, Kath JC, Hulford CA, Autry CL, Luzzio MJ, Ung EJ, Roberts WG, Bonnette PC, Buckbinder L, Mistry A, Griffor MC, Han S, Guzman-Perez A Bioorg Med Chem Lett. 2008 Dec 1;18(23):6071-7. Epub 2008 Oct 11. PMID:18951788<ref>PMID:18951788</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 3et7" style="background-color:#fffaf0;"></div>

==See Also==
*[[Tyrosine kinase 3D structures|Tyrosine kinase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Han S]]