6cw8: Difference between revisions
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==Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 complexed with RTS-V5== | |||
<StructureSection load='6cw8' size='340' side='right' caption='[[6cw8]], [[Resolution|resolution]] 1.90Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6cw8]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Brachidanio_rerio Brachidanio rerio]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CW8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CW8 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FGY:N-(2,2-dimethylpropyl)-N~2~-[4-(hydroxycarbamoyl)benzene-1-carbonyl]-L-asparaginyl-N-benzyl-L-alaninamide'>FGY</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">hdac6 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=7955 Brachidanio rerio])</td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6cw8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cw8 OCA], [http://pdbe.org/6cw8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6cw8 RCSB], [http://www.ebi.ac.uk/pdbsum/6cw8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6cw8 ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Dual- or multi-target drugs have emerged as a promising alternative to combination therapies. Proteasome inhibitors (PIs) possess synergistic activity with histone deacetylase (HDAC) inhibitors due to the simultaneous blockage of the ubiquitin-degradation and aggresome pathways. Here, we present the rational design, synthesis, binding modes and anticancer properties of RTS-V5 as the first-in-class dual HDAC-proteasome ligand. The inhibition of both targets was confirmed by biochemical and cellular assays as well as X-ray crystal structures of the 20S proteasome and HDAC6 complexed with RTS-V5. Cytotoxicity assays with leukemia and multiple myeloma cell lines as well as therapy-refractory primary patient-derived leukemia cells demonstrated that RTS-V5 possesses potent and selective anticancer activity. Our results will thus guide the structure-based optimization of dual HDAC-proteasome inhibitors for the treatment of hematological malignancies. | |||
Discovery of the first-in-class dual histone deacetylase-proteasome inhibitor.,Bhatia S, Krieger V, Groll M, Osko J, Ressing N, Ahlert H, Borkhardt A, Kurz T, Christianson DW, Hauer J, Hansen FK J Med Chem. 2018 Oct 26. doi: 10.1021/acs.jmedchem.8b01487. PMID:30365892<ref>PMID:30365892</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Christianson, D | <div class="pdbe-citations 6cw8" style="background-color:#fffaf0;"></div> | ||
[[Category: Osko, J | == References == | ||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Brachidanio rerio]] | |||
[[Category: Christianson, D W]] | |||
[[Category: Osko, J D]] | |||
[[Category: Histone deacetylase]] | |||
[[Category: Hydrolase]] | |||
[[Category: Metallohydrolase]] | |||
Revision as of 12:30, 16 January 2019
Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 complexed with RTS-V5
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