7jom

Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 complexed with TO-317

spinqualitylabelsall models 7jom, resolution 1.84Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7jom is a 2 chain structure with sequence from Danio rerio. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.84Å Ligands: EDO, FMT, K, TO3, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function F8W4B7_DANRE Publication Abstract from PubMed Histone deacetylase 6 (HDAC6) is involved in multiple regulatory processes, ranging from cellular stress to intracellular transport. Inhibition of aberrant HDAC6 activity in several cancers and neurological diseases has been shown to be efficacious in both preclinical and clinical studies. While selective HDAC6 targeting has been pursued as an alternative to pan-HDAC drugs, identifying truly selective molecular templates has not been trivial. Herein, we report a structure-activity relationship study yielding TO-317, which potently binds HDAC6 catalytic domain 2 (K(i) = 0.7 nM) and inhibits the enzyme function (IC(50) = 2 nM). TO-317 exhibits 158-fold selectivity for HDAC6 over other HDAC isozymes by binding the catalytic Zn(2+) and, uniquely, making a never seen before direct hydrogen bond with the Zn(2+) coordinating residue, His614. This novel structural motif targeting the second-sphere His614 interaction, observed in a 1.84 A resolution crystal structure with drHDAC6 from zebrafish, can provide new pharmacophores for identifying enthalpically driven, high-affinity, HDAC6-selective inhibitors. Unique Molecular Interaction with the Histone Deacetylase 6 Catalytic Tunnel: Crystallographic and Biological Characterization of a Model Chemotype.,Olaoye OO, Watson PR, Nawar N, Geletu M, Sedighi A, Bukhari S, Raouf YS, Manaswiyoungkul P, Erdogan F, Abdeldayem A, Cabral AD, Hassan MM, Toutah K, Shouksmith AE, Gawel JM, Israelian J, Radu TB, Kachhiyapatel N, de Araujo ED, Christianson DW, Gunning PT J Med Chem. 2021 Mar 11;64(5):2691-2704. doi: 10.1021/acs.jmedchem.0c01922. Epub , 2021 Feb 12. PMID:33576627 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Histone deacetylase 3D structures

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