View source for 6wdw


==Crystal Structure of Danio rerio Histone Deacetylase 10 in Complex with Dimethylaminoethylindole Phenylhydroxamate Inhibitor==
<StructureSection load='6wdw' size='340' side='right'caption='[[6wdw]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6wdw]] 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=6WDW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6WDW 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]] 2.2&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=TWV:4-({3-[2-(dimethylamino)ethyl]-1H-indol-1-yl}methyl)-N-hydroxybenzamide'>TWV</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=6wdw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6wdw OCA], [https://pdbe.org/6wdw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6wdw RCSB], [https://www.ebi.ac.uk/pdbsum/6wdw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6wdw 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 ==
The cytosolic class IIb histone deacetylase HDAC10 is an emerging target for drug design. As an inducer of autophagy, its selective inhibition suppresses the autophagic response that otherwise attenuates the efficacy of cytotoxic cancer chemotherapy drugs. HDAC10 is a zinc-dependent polyamine deacetylase exhibiting maximal catalytic activity against N(8)-acetylspermidine. As revealed in the structure of Danio rerio (zebrafish) HDAC10, two conserved structural motifs direct this narrow substrate specificity: a 310 helix containing the P(E,A)CE motif that sterically constricts the active site and an electrostatic "gatekeeper," E274, that confers selectivity for cationic polyamine substrates. To accelerate drug design efforts targeting human HDAC10, we now report the preparation of "humanized" zebrafish HDAC10 in which two amino acid substitutions, A24E and D94A, yield an active site contour more similar to that of human HDAC10. X-ray crystal structures of this HDAC10 variant complexed with Tubastatin A and indole analogues bearing pendant tertiary amines reveal that inhibitors capable of hydrogen bonding with gatekeeper E274 exhibit high affinity and selectivity for HDAC10 over HDAC6 (the other class IIb isozyme). Moreover, these structures reveal that the P(E,A)CE motif helix can shift by up to 2 A to accommodate the binding of bulky inhibitors. Thus, slender polyamine-like inhibitor structures are not exclusively required for selective, high affinity binding to HDAC10. Indeed, the flexibility of the P(E,A)CE motif helix could conceivably enable the binding of certain protein substrates.

Structural Basis for the Selective Inhibition of HDAC10, the Cytosolic Polyamine Deacetylase.,Herbst-Gervasoni CJ, Steimbach RR, Morgen M, Miller AK, Christianson DW ACS Chem Biol. 2020 Jul 23. doi: 10.1021/acschembio.0c00362. PMID:32659072<ref>PMID:32659072</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6wdw" style="background-color:#fffaf0;"></div>

==See Also==
*[[Histone deacetylase 3D structures|Histone deacetylase 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Danio rerio]]
[[Category: Large Structures]]
[[Category: Christianson DW]]
[[Category: Herbst-Gervasoni CJ]]