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==Crystal Structure of Danio rerio Histone Deacetylase 10 in Complex with Piperidine-4-hydroxamic acid Inhibitor== | |||
<StructureSection load='7u59' size='340' side='right'caption='[[7u59]], [[Resolution|resolution]] 2.18Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7u59]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Danio_rerio Danio rerio]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7U59 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7U59 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]] 2.18Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=LDI:~{N}-oxidanyl-1-[2-[(phenylmethyl)amino]ethyl]piperidine-4-carboxamide'>LDI</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=7u59 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7u59 OCA], [https://pdbe.org/7u59 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7u59 RCSB], [https://www.ebi.ac.uk/pdbsum/7u59 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7u59 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/HDA10_DANRE HDA10_DANRE] Polyamine deacetylase (PDAC), which acts preferentially on N(8)-acetylspermidine, and also on acetylcadaverine and acetylputrescine (PubMed:28516954). Exhibits attenuated catalytic activity toward N(1),N(8)-diacetylspermidine and very low activity, if any, toward N(1)-acetylspermidine (PubMed:28516954). Has a very weak lysine deacetylase, if any (PubMed:28516954).<ref>PMID:28516954</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Histone deacetylases (HDACs) are important epigenetic regulators involved in many diseases, especially cancer. Five HDAC inhibitors have been approved for anticancer therapy and many are in clinical trials. Among the 11 zinc-dependent HDACs, HDAC10 has received relatively little attention by drug discovery campaigns, despite its involvement, e. g., in the pathogenesis of neuroblastoma. This is due in part to a lack of robust enzymatic conversion assays. In contrast to the protein lysine deacetylase and deacylase activity of most other HDAC subtypes, it has recently been shown that HDAC10 has strong preferences for deacetylation of oligoamine substrates like acetyl-putrescine or -spermidine. Hence, it is also termed a polyamine deacetylase (PDAC). Here, we present the first fluorescent enzymatic conversion assay for HDAC10 using an aminocoumarin-labelled acetyl-spermidine derivative to measure its PDAC activity, which is suitable for high-throughput screening. Using this assay, we identified potent inhibitors of HDAC10-mediated spermidine deacetylation in vitro. Based on the oligoamine preference of HDAC10, we also designed inhibitors with a basic moiety in appropriate distance to the zinc binding hydroxamate that showed potent inhibition of HDAC10 with high selectivity, and we solved a HDAC10-inhibitor structure using X-ray crystallography. We could demonstrate selective cellular target engagement for HDAC10 but a lysosomal phenotype in neuroblastoma cells that was previously associated with HDAC10 inhibition was not observed. Thus, we have developed new chemical probes for HDAC10 that allow further clarification of the biological role of this enzyme. | |||
First Fluorescent Acetylspermidine Deacetylation Assay for HDAC10 Identifies Selective Inhibitors with Cellular Target Engagement.,Herp D, Ridinger J, Robaa D, Shinsky SA, Schmidtkunz K, Yesiloglu TZ, Bayer T, Steimbach RR, Herbst-Gervasoni CJ, Merz A, Romier C, Sehr P, Gunkel N, Miller AK, Christianson DW, Oehme I, Sippl W, Jung M Chembiochem. 2022 Jul 19;23(14):e202200180. doi: 10.1002/cbic.202200180. Epub , 2022 Jun 10. PMID:35608330<ref>PMID:35608330</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 7u59" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Histone deacetylase 3D structures|Histone deacetylase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Danio rerio]] | |||
[[Category: Large Structures]] | |||
[[Category: Christianson DW]] | |||
[[Category: Herbst-Gervasoni CJ]] | |||
Latest revision as of 14:36, 23 October 2024
Crystal Structure of Danio rerio Histone Deacetylase 10 in Complex with Piperidine-4-hydroxamic acid InhibitorCrystal Structure of Danio rerio Histone Deacetylase 10 in Complex with Piperidine-4-hydroxamic acid Inhibitor
Structural highlights
FunctionHDA10_DANRE Polyamine deacetylase (PDAC), which acts preferentially on N(8)-acetylspermidine, and also on acetylcadaverine and acetylputrescine (PubMed:28516954). Exhibits attenuated catalytic activity toward N(1),N(8)-diacetylspermidine and very low activity, if any, toward N(1)-acetylspermidine (PubMed:28516954). Has a very weak lysine deacetylase, if any (PubMed:28516954).[1] Publication Abstract from PubMedHistone deacetylases (HDACs) are important epigenetic regulators involved in many diseases, especially cancer. Five HDAC inhibitors have been approved for anticancer therapy and many are in clinical trials. Among the 11 zinc-dependent HDACs, HDAC10 has received relatively little attention by drug discovery campaigns, despite its involvement, e. g., in the pathogenesis of neuroblastoma. This is due in part to a lack of robust enzymatic conversion assays. In contrast to the protein lysine deacetylase and deacylase activity of most other HDAC subtypes, it has recently been shown that HDAC10 has strong preferences for deacetylation of oligoamine substrates like acetyl-putrescine or -spermidine. Hence, it is also termed a polyamine deacetylase (PDAC). Here, we present the first fluorescent enzymatic conversion assay for HDAC10 using an aminocoumarin-labelled acetyl-spermidine derivative to measure its PDAC activity, which is suitable for high-throughput screening. Using this assay, we identified potent inhibitors of HDAC10-mediated spermidine deacetylation in vitro. Based on the oligoamine preference of HDAC10, we also designed inhibitors with a basic moiety in appropriate distance to the zinc binding hydroxamate that showed potent inhibition of HDAC10 with high selectivity, and we solved a HDAC10-inhibitor structure using X-ray crystallography. We could demonstrate selective cellular target engagement for HDAC10 but a lysosomal phenotype in neuroblastoma cells that was previously associated with HDAC10 inhibition was not observed. Thus, we have developed new chemical probes for HDAC10 that allow further clarification of the biological role of this enzyme. First Fluorescent Acetylspermidine Deacetylation Assay for HDAC10 Identifies Selective Inhibitors with Cellular Target Engagement.,Herp D, Ridinger J, Robaa D, Shinsky SA, Schmidtkunz K, Yesiloglu TZ, Bayer T, Steimbach RR, Herbst-Gervasoni CJ, Merz A, Romier C, Sehr P, Gunkel N, Miller AK, Christianson DW, Oehme I, Sippl W, Jung M Chembiochem. 2022 Jul 19;23(14):e202200180. doi: 10.1002/cbic.202200180. Epub , 2022 Jun 10. PMID:35608330[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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