| 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.[1] [2] [3] [4]
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[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Hu E, Chen Z, Fredrickson T, Zhu Y, Kirkpatrick R, Zhang GF, Johanson K, Sung CM, Liu R, Winkler J. Cloning and characterization of a novel human class I histone deacetylase that functions as a transcription repressor. J Biol Chem. 2000 May 19;275(20):15254-64. PMID:10748112 doi:https://dx.doi.org/10.1074/jbc.M908988199
- ↑ Buggy JJ, Sideris ML, Mak P, Lorimer DD, McIntosh B, Clark JM. Cloning and characterization of a novel human histone deacetylase, HDAC8. Biochem J. 2000 Aug 15;350 Pt 1:199-205. PMID:10926844
- ↑ Van den Wyngaert I, de Vries W, Kremer A, Neefs J, Verhasselt P, Luyten WH, Kass SU. Cloning and characterization of human histone deacetylase 8. FEBS Lett. 2000 Jul 28;478(1-2):77-83. PMID:10922473
- ↑ Lee H, Rezai-Zadeh N, Seto E. Negative regulation of histone deacetylase 8 activity by cyclic AMP-dependent protein kinase A. Mol Cell Biol. 2004 Jan;24(2):765-73. PMID:14701748
- ↑ Cole KE, Dowling DP, Boone MA, Phillips AJ, Christianson DW. Structural basis of the antiproliferative activity of largazole, a depsipeptide inhibitor of the histone deacetylases. J Am Chem Soc. 2011 Aug 17;133(32):12474-7. Epub 2011 Jul 26. PMID:21790156 doi:10.1021/ja205972n
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