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'''Unreleased structure'''


The entry 6hmr is ON HOLD  until Paper Publication
==Crystal structure of human Casein Kinase I delta in complex with a photoswitchable 2-Azothiazole-based inhibitor (compound 2)==
<StructureSection load='6hmr' size='340' side='right'caption='[[6hmr]], [[Resolution|resolution]] 1.78&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6hmr]] is a 2 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=6HMR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6HMR 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]] 1.782&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GE5:3-(2,5-dimethoxyphenyl)-~{N}-[4-[4-(4-fluorophenyl)-2-[(~{E})-phenyldiazenyl]-1,3-thiazol-5-yl]pyridin-2-yl]propanamide'>GE5</scene>, <scene name='pdbligand=MLA:MALONIC+ACID'>MLA</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=6hmr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6hmr OCA], [https://pdbe.org/6hmr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6hmr RCSB], [https://www.ebi.ac.uk/pdbsum/6hmr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6hmr ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/KC1D_HUMAN KC1D_HUMAN] Familial advanced sleep-phase syndrome. The disease is caused by mutations affecting the gene represented in this entry.
== Function ==
[https://www.uniprot.org/uniprot/KC1D_HUMAN KC1D_HUMAN] Essential serine/threonine-protein kinase that regulates diverse cellular growth and survival processes including Wnt signaling, DNA repair and circadian rhythms. It can phosphorylate a large number of proteins. Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. Phosphorylates connexin-43/GJA1, MAP1A, SNAPIN, MAPT/TAU, TOP2A, DCK, HIF1A, EIF6, p53/TP53, DVL2, DVL3, ESR1, AIB1/NCOA3, DNMT1, PKD2, YAP1, PER1 and PER2. Central component of the circadian clock. May act as a negative regulator of circadian rhythmicity by phosphorylating PER1 and PER2, leading to retain PER1 in the cytoplasm. YAP1 phosphorylation promotes its SCF(beta-TRCP) E3 ubiquitin ligase-mediated ubiquitination and subsequent degradation. DNMT1 phosphorylation reduces its DNA-binding activity. Phosphorylation of ESR1 and AIB1/NCOA3 stimulates their activity and coactivation. Phosphorylation of DVL2 and DVL3 regulates WNT3A signaling pathway that controls neurite outgrowth. EIF6 phosphorylation promotes its nuclear export. Triggers down-regulation of dopamine receptors in the forebrain. Activates DCK in vitro by phosphorylation. TOP2A phosphorylation favors DNA cleavable complex formation. May regulate the formation of the mitotic spindle apparatus in extravillous trophoblast. Modulates connexin-43/GJA1 gap junction assembly by phosphorylation. Probably involved in lymphocyte physiology. Regulates fast synaptic transmission mediated by glutamate.<ref>PMID:10606744</ref> <ref>PMID:12270943</ref> <ref>PMID:14761950</ref> <ref>PMID:16027726</ref> <ref>PMID:17962809</ref> <ref>PMID:17562708</ref> <ref>PMID:19043076</ref> <ref>PMID:19339517</ref> <ref>PMID:20637175</ref> <ref>PMID:20041275</ref> <ref>PMID:20048001</ref> <ref>PMID:20699359</ref> <ref>PMID:20696890</ref> <ref>PMID:20407760</ref> <ref>PMID:21084295</ref> <ref>PMID:21422228</ref>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
In photopharmacology, photoswitchable compounds including azobenzene or other diarylazo moieties exhibit bioactivity against a target protein typically in the slender E-configuration, whereas the rather bulky Z-configuration usually is pharmacologically less potent. Herein we report the design, synthesis and photochemical/inhibitory characterization of new photoswitchable kinase inhibitors targeting p38alpha MAPK and CK1delta. A well characterized inhibitor scaffold was used to attach arylazo- and diazocine moieties. When the isolated isomers, or the photostationary state (PSS) of isomers, were tested in commonly used in vitro kinase assays, however, only small differences in activity were observed. X-ray analyses of ligand-bound p38alpha MAPK and CK1delta complexes revealed dynamic conformational adaptations of the protein with respect to both isomers. More importantly, irreversible reduction of the azo group to the corresponding hydrazine was observed. Independent experiments revealed that reducing agents such as DTT (dithiothreitol) and GSH (glutathione) that are typically used for protein stabilization in biological assays were responsible. Two further sources of error are the concentration dependence of the E-Z-switching efficiency and artefacts due to incomplete exclusion of light during testing. Our findings may also apply to a number of previously investigated azobenzene-based photoswitchable inhibitors.


Authors: Pichlo, C., Schehr, M., Charl, J., Brunstein, E., Peifer, C., Baumann, U.
2-Azo-, 2-diazocine-thiazols and 2-azo-imidazoles as photoswitchable kinase inhibitors: limitations and pitfalls of the photoswitchable inhibitor approach.,Schehr M, Ianes C, Weisner J, Heintze L, Muller MP, Pichlo C, Charl J, Brunstein E, Ewert J, Lehr M, Baumann U, Rauh D, Knippschild U, Peifer C, Herges R Photochem Photobiol Sci. 2019 Mar 29. doi: 10.1039/c9pp00010k. PMID:30924488<ref>PMID:30924488</ref>


Description: Crystal structure of human Casein Kinase I delta in complex with a photoswitchable 2-Azothiazole-based inhibitor (compound 2)
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
[[Category: Peifer, C]]
<div class="pdbe-citations 6hmr" style="background-color:#fffaf0;"></div>
[[Category: Schehr, M]]
 
[[Category: Baumann, U]]
==See Also==
[[Category: Pichlo, C]]
*[[Casein kinase 3D structures|Casein kinase 3D structures]]
[[Category: Charl, J]]
== References ==
[[Category: Brunstein, E]]
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Baumann U]]
[[Category: Brunstein E]]
[[Category: Charl J]]
[[Category: Peifer C]]
[[Category: Pichlo C]]
[[Category: Schehr M]]

Latest revision as of 14:33, 24 January 2024

Crystal structure of human Casein Kinase I delta in complex with a photoswitchable 2-Azothiazole-based inhibitor (compound 2)Crystal structure of human Casein Kinase I delta in complex with a photoswitchable 2-Azothiazole-based inhibitor (compound 2)

Structural highlights

6hmr is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.782Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

KC1D_HUMAN Familial advanced sleep-phase syndrome. The disease is caused by mutations affecting the gene represented in this entry.

Function

KC1D_HUMAN Essential serine/threonine-protein kinase that regulates diverse cellular growth and survival processes including Wnt signaling, DNA repair and circadian rhythms. It can phosphorylate a large number of proteins. Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. Phosphorylates connexin-43/GJA1, MAP1A, SNAPIN, MAPT/TAU, TOP2A, DCK, HIF1A, EIF6, p53/TP53, DVL2, DVL3, ESR1, AIB1/NCOA3, DNMT1, PKD2, YAP1, PER1 and PER2. Central component of the circadian clock. May act as a negative regulator of circadian rhythmicity by phosphorylating PER1 and PER2, leading to retain PER1 in the cytoplasm. YAP1 phosphorylation promotes its SCF(beta-TRCP) E3 ubiquitin ligase-mediated ubiquitination and subsequent degradation. DNMT1 phosphorylation reduces its DNA-binding activity. Phosphorylation of ESR1 and AIB1/NCOA3 stimulates their activity and coactivation. Phosphorylation of DVL2 and DVL3 regulates WNT3A signaling pathway that controls neurite outgrowth. EIF6 phosphorylation promotes its nuclear export. Triggers down-regulation of dopamine receptors in the forebrain. Activates DCK in vitro by phosphorylation. TOP2A phosphorylation favors DNA cleavable complex formation. May regulate the formation of the mitotic spindle apparatus in extravillous trophoblast. Modulates connexin-43/GJA1 gap junction assembly by phosphorylation. Probably involved in lymphocyte physiology. Regulates fast synaptic transmission mediated by glutamate.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16]

Publication Abstract from PubMed

In photopharmacology, photoswitchable compounds including azobenzene or other diarylazo moieties exhibit bioactivity against a target protein typically in the slender E-configuration, whereas the rather bulky Z-configuration usually is pharmacologically less potent. Herein we report the design, synthesis and photochemical/inhibitory characterization of new photoswitchable kinase inhibitors targeting p38alpha MAPK and CK1delta. A well characterized inhibitor scaffold was used to attach arylazo- and diazocine moieties. When the isolated isomers, or the photostationary state (PSS) of isomers, were tested in commonly used in vitro kinase assays, however, only small differences in activity were observed. X-ray analyses of ligand-bound p38alpha MAPK and CK1delta complexes revealed dynamic conformational adaptations of the protein with respect to both isomers. More importantly, irreversible reduction of the azo group to the corresponding hydrazine was observed. Independent experiments revealed that reducing agents such as DTT (dithiothreitol) and GSH (glutathione) that are typically used for protein stabilization in biological assays were responsible. Two further sources of error are the concentration dependence of the E-Z-switching efficiency and artefacts due to incomplete exclusion of light during testing. Our findings may also apply to a number of previously investigated azobenzene-based photoswitchable inhibitors.

2-Azo-, 2-diazocine-thiazols and 2-azo-imidazoles as photoswitchable kinase inhibitors: limitations and pitfalls of the photoswitchable inhibitor approach.,Schehr M, Ianes C, Weisner J, Heintze L, Muller MP, Pichlo C, Charl J, Brunstein E, Ewert J, Lehr M, Baumann U, Rauh D, Knippschild U, Peifer C, Herges R Photochem Photobiol Sci. 2019 Mar 29. doi: 10.1039/c9pp00010k. PMID:30924488[17]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Dumaz N, Milne DM, Meek DW. Protein kinase CK1 is a p53-threonine 18 kinase which requires prior phosphorylation of serine 15. FEBS Lett. 1999 Dec 17;463(3):312-6. PMID:10606744
  2. ↑ Cooper CD, Lampe PD. Casein kinase 1 regulates connexin-43 gap junction assembly. J Biol Chem. 2002 Nov 22;277(47):44962-8. Epub 2002 Sep 20. PMID:12270943 doi:10.1074/jbc.M209427200
  3. ↑ Li G, Yin H, Kuret J. Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules. J Biol Chem. 2004 Apr 16;279(16):15938-45. Epub 2004 Feb 2. PMID:14761950 doi:10.1074/jbc.M314116200
  4. ↑ Stoter M, Bamberger AM, Aslan B, Kurth M, Speidel D, Loning T, Frank HG, Kaufmann P, Lohler J, Henne-Bruns D, Deppert W, Knippschild U. Inhibition of casein kinase I delta alters mitotic spindle formation and induces apoptosis in trophoblast cells. Oncogene. 2005 Dec 1;24(54):7964-75. PMID:16027726 doi:10.1038/sj.onc.1208941
  5. ↑ von Blume J, Knippschild U, Dequiedt F, Giamas G, Beck A, Auer A, Van Lint J, Adler G, Seufferlein T. Phosphorylation at Ser244 by CK1 determines nuclear localization and substrate targeting of PKD2. EMBO J. 2007 Nov 14;26(22):4619-33. Epub 2007 Oct 25. PMID:17962809 doi:10.1038/sj.emboj.7601891
  6. ↑ Hanger DP, Byers HL, Wray S, Leung KY, Saxton MJ, Seereeram A, Reynolds CH, Ward MA, Anderton BH. Novel phosphorylation sites in tau from Alzheimer brain support a role for casein kinase 1 in disease pathogenesis. J Biol Chem. 2007 Aug 10;282(32):23645-54. Epub 2007 Jun 11. PMID:17562708 doi:10.1074/jbc.M703269200
  7. ↑ Grozav AG, Chikamori K, Kozuki T, Grabowski DR, Bukowski RM, Willard B, Kinter M, Andersen AH, Ganapathi R, Ganapathi MK. Casein kinase I delta/epsilon phosphorylates topoisomerase IIalpha at serine-1106 and modulates DNA cleavage activity. Nucleic Acids Res. 2009 Feb;37(2):382-92. doi: 10.1093/nar/gkn934. Epub 2008 Nov , 29. PMID:19043076 doi:10.1093/nar/gkn934
  8. ↑ Giamas G, Castellano L, Feng Q, Knippschild U, Jacob J, Thomas RS, Coombes RC, Smith CL, Jiao LR, Stebbing J. CK1delta modulates the transcriptional activity of ERalpha via AIB1 in an estrogen-dependent manner and regulates ERalpha-AIB1 interactions. Nucleic Acids Res. 2009 May;37(9):3110-23. doi: 10.1093/nar/gkp136. Epub 2009 Apr, 1. PMID:19339517 doi:10.1093/nar/gkp136
  9. ↑ Smal C, Vertommen D, Amsailale R, Arts A, Degand H, Morsomme P, Rider MH, Neste EV, Bontemps F. Casein kinase 1delta activates human recombinant deoxycytidine kinase by Ser-74 phosphorylation, but is not involved in the in vivo regulation of its activity. Arch Biochem Biophys. 2010 Oct 1;502(1):44-52. doi: 10.1016/j.abb.2010.07.009., Epub 2010 Jul 14. PMID:20637175 doi:10.1016/j.abb.2010.07.009
  10. ↑ Venerando A, Marin O, Cozza G, Bustos VH, Sarno S, Pinna LA. Isoform specific phosphorylation of p53 by protein kinase CK1. Cell Mol Life Sci. 2010 Apr;67(7):1105-18. doi: 10.1007/s00018-009-0236-7. Epub, 2009 Dec 30. PMID:20041275 doi:10.1007/s00018-009-0236-7
  11. ↑ Zhao B, Li L, Tumaneng K, Wang CY, Guan KL. A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP). Genes Dev. 2010 Jan 1;24(1):72-85. doi: 10.1101/gad.1843810. PMID:20048001 doi:10.1101/gad.1843810
  12. ↑ Kalousi A, Mylonis I, Politou AS, Chachami G, Paraskeva E, Simos G. Casein kinase 1 regulates human hypoxia-inducible factor HIF-1. J Cell Sci. 2010 Sep 1;123(Pt 17):2976-86. doi: 10.1242/jcs.068122. Epub 2010 Aug, 10. PMID:20699359 doi:10.1242/jcs.068122
  13. ↑ Meng QJ, Maywood ES, Bechtold DA, Lu WQ, Li J, Gibbs JE, Dupre SM, Chesham JE, Rajamohan F, Knafels J, Sneed B, Zawadzke LE, Ohren JF, Walton KM, Wager TT, Hastings MH, Loudon AS. Entrainment of disrupted circadian behavior through inhibition of casein kinase 1 (CK1) enzymes. Proc Natl Acad Sci U S A. 2010 Aug 24;107(34):15240-5. doi:, 10.1073/pnas.1005101107. Epub 2010 Aug 9. PMID:20696890 doi:10.1073/pnas.1005101107
  14. ↑ Sprouse J, Reynolds L, Kleiman R, Tate B, Swanson TA, Pickard GE. Chronic treatment with a selective inhibitor of casein kinase I delta/epsilon yields cumulative phase delays in circadian rhythms. Psychopharmacology (Berl). 2010 Jul;210(4):569-76. doi:, 10.1007/s00213-010-1860-5. Epub 2010 Apr 21. PMID:20407760 doi:10.1007/s00213-010-1860-5
  15. ↑ Biswas A, Mukherjee S, Das S, Shields D, Chow CW, Maitra U. Opposing action of casein kinase 1 and calcineurin in nucleo-cytoplasmic shuttling of mammalian translation initiation factor eIF6. J Biol Chem. 2011 Jan 28;286(4):3129-38. doi: 10.1074/jbc.M110.188565. Epub 2010 , Nov 17. PMID:21084295 doi:10.1074/jbc.M110.188565
  16. ↑ Greer YE, Rubin JS. Casein kinase 1 delta functions at the centrosome to mediate Wnt-3a-dependent neurite outgrowth. J Cell Biol. 2011 Mar 21;192(6):993-1004. doi: 10.1083/jcb.201011111. PMID:21422228 doi:10.1083/jcb.201011111
  17. ↑ Schehr M, Ianes C, Weisner J, Heintze L, Muller MP, Pichlo C, Charl J, Brunstein E, Ewert J, Lehr M, Baumann U, Rauh D, Knippschild U, Peifer C, Herges R. 2-Azo-, 2-diazocine-thiazols and 2-azo-imidazoles as photoswitchable kinase inhibitors: limitations and pitfalls of the photoswitchable inhibitor approach. Photochem Photobiol Sci. 2019 Mar 29. doi: 10.1039/c9pp00010k. PMID:30924488 doi:http://dx.doi.org/10.1039/c9pp00010k

6hmr, resolution 1.78Å

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