4i6h: Difference between revisions

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== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4i6h]] 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=4I6H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4I6H FirstGlance]. <br>
<table><tr><td colspan='2'>[[4i6h]] 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=4I6H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4I6H FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1C8:(7R)-8-CYCLOPENTYL-7-ETHYL-5-METHYL-2-[2-(1,3-THIAZOL-4-YL)-1H-IMIDAZOL-1-YL]-7,8-DIHYDROPTERIDIN-6(5H)-ONE'>1C8</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.91&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1C8:(7R)-8-CYCLOPENTYL-7-ETHYL-5-METHYL-2-[2-(1,3-THIAZOL-4-YL)-1H-IMIDAZOL-1-YL]-7,8-DIHYDROPTERIDIN-6(5H)-ONE'>1C8</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=4i6h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4i6h OCA], [https://pdbe.org/4i6h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4i6h RCSB], [https://www.ebi.ac.uk/pdbsum/4i6h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4i6h ProSAT]</span></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=4i6h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4i6h OCA], [https://pdbe.org/4i6h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4i6h RCSB], [https://www.ebi.ac.uk/pdbsum/4i6h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4i6h ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[https://www.uniprot.org/uniprot/PLK2_HUMAN PLK2_HUMAN] Tumor suppressor serine/threonine-protein kinase involved in synaptic plasticity, centriole duplication and G1/S phase transition. Polo-like kinases act by binding and phosphorylating proteins are that already phosphorylated on a specific motif recognized by the POLO box domains. Phosphorylates CENPJ, NPM1, RAPGEF2, RASGRF1, SNCA, SIPA1L1 and SYNGAP1. Plays a key role in synaptic plasticity and memory by regulating the Ras and Rap protein signaling: required for overactivity-dependent spine remodeling by phosphorylating the Ras activator RASGRF1 and the Rap inhibitor SIPA1L1 leading to their degradation by the proteasome. Conversely, phosphorylates the Rap activator RAPGEF2 and the Ras inhibitor SYNGAP1, promoting their activity. Also regulates synaptic plasticity independently of kinase activity, via its interaction with NSF that disrupts the interaction between NSF and the GRIA2 subunit of AMPARs, leading to a rapid rundown of AMPAR-mediated current that occludes long term depression. Required for procentriole formation and centriole duplication by phosphorylating CENPJ and NPM1, respectively. Its induction by p53/TP53 suggests that it may participate in the mitotic checkpoint following stress.<ref>PMID:15242618</ref> <ref>PMID:19001868</ref> <ref>PMID:20531387</ref> <ref>PMID:20352051</ref>  
[https://www.uniprot.org/uniprot/PLK2_HUMAN PLK2_HUMAN] Tumor suppressor serine/threonine-protein kinase involved in synaptic plasticity, centriole duplication and G1/S phase transition. Polo-like kinases act by binding and phosphorylating proteins are that already phosphorylated on a specific motif recognized by the POLO box domains. Phosphorylates CENPJ, NPM1, RAPGEF2, RASGRF1, SNCA, SIPA1L1 and SYNGAP1. Plays a key role in synaptic plasticity and memory by regulating the Ras and Rap protein signaling: required for overactivity-dependent spine remodeling by phosphorylating the Ras activator RASGRF1 and the Rap inhibitor SIPA1L1 leading to their degradation by the proteasome. Conversely, phosphorylates the Rap activator RAPGEF2 and the Ras inhibitor SYNGAP1, promoting their activity. Also regulates synaptic plasticity independently of kinase activity, via its interaction with NSF that disrupts the interaction between NSF and the GRIA2 subunit of AMPARs, leading to a rapid rundown of AMPAR-mediated current that occludes long term depression. Required for procentriole formation and centriole duplication by phosphorylating CENPJ and NPM1, respectively. Its induction by p53/TP53 suggests that it may participate in the mitotic checkpoint following stress.<ref>PMID:15242618</ref> <ref>PMID:19001868</ref> <ref>PMID:20531387</ref> <ref>PMID:20352051</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Polo-like kinase-2 (Plk-2) has been implicated as the dominant kinase involved in the phosphorylation of alpha-synuclein in Lewy bodies, which are one of the hallmarks of Parkinson's disease neuropathology. Potent, selective, brain-penetrant inhibitors of Plk-2 were obtained from a structure-guided drug discovery approach driven by the first reported Plk-2-inhibitor complexes. The best of these compounds showed excellent isoform and kinome-wide selectivity, with physicochemical properties sufficient to interrogate the role of Plk-2 inhibition in vivo. One such compound significantly decreased phosphorylation of alpha-synuclein in rat brain upon oral administration and represents a useful probe for future studies of this therapeutic avenue toward the potential treatment of Parkinson's disease.
Selective and Brain-Permeable Polo-like Kinase-2 (Plk-2) Inhibitors That Reduce alpha-Synuclein Phosphorylation in Rat Brain.,Aubele DL, Hom RK, Adler M, Galemmo RA Jr, Bowers S, Truong AP, Pan H, Beroza P, Neitz RJ, Yao N, Lin M, Tonn G, Zhang H, Bova MP, Ren Z, Tam D, Ruslim L, Baker J, Diep L, Fitzgerald K, Hoffman J, Motter R, Fauss D, Tanaka P, Dappen M, Jagodzinski J, Chan W, Konradi AW, Latimer L, Zhu YL, Sham HL, Anderson JP, Bergeron M, Artis DR ChemMedChem. 2013 Aug;8(8):1295-313. doi: 10.1002/cmdc.201300166. Epub 2013 Jun, 21. PMID:23794260<ref>PMID:23794260</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4i6h" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==

Latest revision as of 14:50, 1 March 2024

Selective & Brain-Permeable Polo-like Kinase-2 (Plk-2) Inhibitors that Reduce alpha-Synuclein Phosphorylation in Rat BrainSelective & Brain-Permeable Polo-like Kinase-2 (Plk-2) Inhibitors that Reduce alpha-Synuclein Phosphorylation in Rat Brain

Structural highlights

4i6h is a 1 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 1.91Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PLK2_HUMAN Tumor suppressor serine/threonine-protein kinase involved in synaptic plasticity, centriole duplication and G1/S phase transition. Polo-like kinases act by binding and phosphorylating proteins are that already phosphorylated on a specific motif recognized by the POLO box domains. Phosphorylates CENPJ, NPM1, RAPGEF2, RASGRF1, SNCA, SIPA1L1 and SYNGAP1. Plays a key role in synaptic plasticity and memory by regulating the Ras and Rap protein signaling: required for overactivity-dependent spine remodeling by phosphorylating the Ras activator RASGRF1 and the Rap inhibitor SIPA1L1 leading to their degradation by the proteasome. Conversely, phosphorylates the Rap activator RAPGEF2 and the Ras inhibitor SYNGAP1, promoting their activity. Also regulates synaptic plasticity independently of kinase activity, via its interaction with NSF that disrupts the interaction between NSF and the GRIA2 subunit of AMPARs, leading to a rapid rundown of AMPAR-mediated current that occludes long term depression. Required for procentriole formation and centriole duplication by phosphorylating CENPJ and NPM1, respectively. Its induction by p53/TP53 suggests that it may participate in the mitotic checkpoint following stress.[1] [2] [3] [4]

See Also

References

  1. ↑ Warnke S, Kemmler S, Hames RS, Tsai HL, Hoffmann-Rohrer U, Fry AM, Hoffmann I. Polo-like kinase-2 is required for centriole duplication in mammalian cells. Curr Biol. 2004 Jul 13;14(13):1200-7. PMID:15242618 doi:10.1016/j.cub.2004.06.059
  2. ↑ Cizmecioglu O, Warnke S, Arnold M, Duensing S, Hoffmann I. Plk2 regulated centriole duplication is dependent on its localization to the centrioles and a functional polo-box domain. Cell Cycle. 2008 Nov 15;7(22):3548-55. Epub 2008 Nov 26. PMID:19001868
  3. ↑ Chang J, Cizmecioglu O, Hoffmann I, Rhee K. PLK2 phosphorylation is critical for CPAP function in procentriole formation during the centrosome cycle. EMBO J. 2010 Jul 21;29(14):2395-406. doi: 10.1038/emboj.2010.118. Epub 2010 Jun, 8. PMID:20531387 doi:10.1038/emboj.2010.118
  4. ↑ Krause A, Hoffmann I. Polo-like kinase 2-dependent phosphorylation of NPM/B23 on serine 4 triggers centriole duplication. PLoS One. 2010 Mar 24;5(3):e9849. doi: 10.1371/journal.pone.0009849. PMID:20352051 doi:10.1371/journal.pone.0009849

4i6h, resolution 1.91Å

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