HDAC8 is a Zn-dependent class I histone deacetylase that catalyzes hydrolysis of an N(6)-acetyl-lysine residue of a histone to yield a deacetylated histone (EC 3.5.1.98). Histone acetylation/deacetylation process is important for mediation of transcriptional regulation of many genes. Histone deacetylases usually act via association with DNA binding proteins to target specific chromatin regions. HDAC8 is found in human cytoskeleton-bound protein fraction and insoluble cell pellets. It plays a crucial role in intramembraneous bone formation; germline deletion of HDAC8 is detrimental to skull bone formation. HDAC8 is possibly associated with the smooth muscle actin cytockeleton and may regulate the contractive capacity of smooth muscle cells. HDAC8 is also involved in the metabolic control of the estrogen receptor related receptor (ERR)-alpha/peroxisome proliferator activated receptor (PPAR) gamma coactivator 1 alpha (PGC1-alpha) transcriptional complex as well as in the development of neuroblastoma and T-cell lymphoma. HDAC8-selective small-molecule inhibitors could be a therapeutic drug option for these diseases.
Comment:Active site includes Zn binding site, lipophilic tube and foot pocket.
Comment:Active site consists of a long narrow tunnel (that serves for substrate binding) and a cavity with Zn ion (important for catalysis).
Comment:Bound subtrate is a p53-derived diacetylated peptide, (acetyl)-L,Arg-L,His-L,Lys(e-acetyl)-L,Lys(e-acetyl), containing a fluorogenic coumarin group at its carboxyl terminus.
Structure:2V5W: Human histone deacetylase 8 (HDAC8) binds an acetylated peptidic substrate; contacts at 4.0A.
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