View source for 3bhy


==Crystal structure of human death associated protein kinase 3 (DAPK3) in complex with a beta-carboline ligand==
<StructureSection load='3bhy' size='340' side='right'caption='[[3bhy]], [[Resolution|resolution]] 1.24&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3bhy]] 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=3BHY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3BHY 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]] 1.24&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7CP:(4R)-7,8-DICHLORO-1,9-DIMETHYL-1-OXO-1,2,4,9-TETRAHYDROSPIRO[BETA-CARBOLINE-3,4-PIPERIDINE]-4-CARBONITRILE'>7CP</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</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=3bhy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3bhy OCA], [https://pdbe.org/3bhy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3bhy RCSB], [https://www.ebi.ac.uk/pdbsum/3bhy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3bhy ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/DAPK3_HUMAN DAPK3_HUMAN] Serine/threonine kinase which is involved in the regulation of apoptosis, autophagy, transcription, translation, actin cytoskeleton reorganization, cell motility, smooth muscle contraction, and mitosis, particularly cytokinesis. Regulates both type I apoptotic and type II autophagic cell deaths signal, depending on the cellular setting. The former is caspase-dependent, while the latter is caspase-independent and is characterized by the accumulation of autophagic vesicles. Regulates myosin phosphorylation in both smooth muscle and non-muscle cells. In smooth muscle, regulates myosin either directly by phosphorylating MYL12B and MYL9 or through inhibition of smooth muscle myosin phosphatase (SMPP1M) via phosphorylation of PPP1R12A, and the inhibition of SMPP1M functions to enhance muscle responsiveness to Ca(2+) and promote a contractile state. Enhances transcription from AR-responsive promoters in a hormone- and kinase-dependent manner. Phosphorylates STAT3 and enhances its transcriptional activity. Positively regulates the canonical Wnt/beta-catenin signaling through interaction with NLK and TCF7L2. Can disrupt the NLK-TCF7L2 complex thereby influencing the phosphorylation of TCF7L2 by NLK. Phosphorylates histone H3 on 'Thr-11' at centromeres during mitosis. Involved in the formation of promyelocytic leukemia protein nuclear body (PML-NB), one of many subnuclear domains in the eukaryotic cell nucleus, and which is involved in oncogenesis and viral infection. Phosphorylates RPL13A on 'Ser-77' upon interferon-gamma activation which is causing RPL13A release from the ribosome, its association with the GAIT complex and its subsequent involvement in transcript-selective translation inhibition.<ref>PMID:10356987</ref> <ref>PMID:17126281</ref> <ref>PMID:12917339</ref> <ref>PMID:12560483</ref> <ref>PMID:15367680</ref> <ref>PMID:18995835</ref> <ref>PMID:16219639</ref> <ref>PMID:17158456</ref> <ref>PMID:18515077</ref> <ref>PMID:18084323</ref> <ref>PMID:21454679</ref> <ref>PMID:21408167</ref>   Isoform 2 can phosphorylate myosin, PPP1R12A and MYL12B.<ref>PMID:10356987</ref> <ref>PMID:17126281</ref> <ref>PMID:12917339</ref> <ref>PMID:12560483</ref> <ref>PMID:15367680</ref> <ref>PMID:18995835</ref> <ref>PMID:16219639</ref> <ref>PMID:17158456</ref> <ref>PMID:18515077</ref> <ref>PMID:18084323</ref> <ref>PMID:21454679</ref> <ref>PMID:21408167</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/bh/3bhy_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=3bhy ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Development of both potent and selective kinase inhibitors is a challenging task in modern drug discovery. The innate promiscuity of kinase inhibitors largely results from ATP-mimetic binding to the kinase hinge region. We present a novel class of substituted 7,8-dichloro-1-oxo-beta-carbolines based on the distinct structural features of the alkaloid bauerine C whose kinase inhibitory activity does not rely on canonical ATP-mimetic hinge interactions. Intriguingly, cocrystal structures revealed an unexpected inverted binding mode and the presence of halogen bonds with kinase backbone residues. The compounds exhibit excellent selectivity over a comprehensive panel of human protein kinases while inhibiting selected kinases such as the oncogenic PIM1 at low nanomolar concentrations. Together, our biochemical and structural data suggest that this scaffold may serve as a valuable template for the design and development of specific inhibitors of various kinases including the PIM family of kinases, CLKs, DAPK3 (ZIPK), BMP2K (BIKE), and others.

7,8-Dichloro-1-oxo-beta-carbolines as a Versatile Scaffold for the Development of Potent and Selective Kinase Inhibitors with Unusual Binding Modes.,Huber K, Brault L, Fedorov O, Gasser C, Filippakopoulos P, Bullock AN, Fabbro D, Trappe J, Schwaller J, Knapp S, Bracher F J Med Chem. 2012 Jan 12;55(1):403-13. Epub 2012 Jan 3. PMID:22136433<ref>PMID:22136433</ref>

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

==See Also==
*[[Death-associated protein kinase 3D structures|Death-associated protein kinase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Arrowsmith CH]]
[[Category: Berridge G]]
[[Category: Bracher F]]
[[Category: Edwards AM]]
[[Category: Eswaran J]]
[[Category: Fedorov O]]
[[Category: Filippakopoulos P]]
[[Category: Huber K]]
[[Category: Knapp S]]
[[Category: Niesen F]]
[[Category: Pike ACW]]
[[Category: Rellos P]]
[[Category: Roos A]]
[[Category: Weigelt J]]
[[Category: Von Delft F]]