6cw8 | pdb_00006cw8

Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 complexed with RTS-V5

spinqualitylabelsall models 6cw8, resolution 1.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6cw8 is a 2 chain structure with sequence from Brachidanio rerio. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: EDO, FGY, K, ZN Gene: hdac6 (Brachidanio rerio) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Histone deacetylase 3D structures

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