3rqd | pdb_00003rqd

Ideal Thiolate-Zinc Coordination Geometry in Depsipeptide Binding to Histone Deacetylase 8

spinqualitylabelsall models 3rqd, resolution 2.14Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3rqd is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: K, ZN NonStd Res: 02G, 03Y, BB9 Gene: HDAC8, HDACL1, CDA07 (HUMAN) Activity: Histone deacetylase, with EC number 3.5.1.98 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [HDAC8_HUMAN] Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. May play a role in smooth muscle cell contractility. Publication Abstract from PubMed Largazole is a macrocyclic depsipeptide originally isolated from the marine cyanobacterium Symploca sp., which is indigenous to the warm, blue-green waters of Key Largo, Florida (whence largazole derives its name). Largazole contains an unusual thiazoline-thiazole ring system that rigidifies its macrocyclic skeleton, and it also contains a lipophilic thioester side chain. Hydrolysis of the thioester in vivo yields largazole thiol, which exhibits remarkable antiproliferative effects and is believed to be the most potent inhibitor of the metal-dependent histone deacetylases (HDACs). Here, the 2.14 A-resolution crystal structure of the HDAC8-largazole thiol complex is the first of an HDAC complexed with a macrocyclic inhibitor and reveals that ideal thiolate-zinc coordination geometry is the key chemical feature responsible for its exceptional affinity and biological activity. Notably, the core structure of largazole is conserved in romidepsin, a depsipeptide natural product formulated as the drug Istodax recently approved for cancer chemotherapy. Accordingly, the structure of the HDAC8-largazole thiol complex is the first to illustrate the mode of action of a new class of therapeutically important HDAC inhibitors. Structural basis of the antiproliferative activity of largazole, a depsipeptide inhibitor of the histone deacetylases.,Cole KE, Dowling DP, Boone MA, Phillips AJ, Christianson DW J Am Chem Soc. 2011 Aug 17;133(32):12474-7. Epub 2011 Jul 26. PMID:21790156 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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