| Structural highlights
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
Metal-dependent histone deacetylases (HDACs) are key epigenetic regulators that represent promising therapeutic targets for the treatment of numerous human diseases. Yet, the currently FDA-approved HDAC inhibitors non-specifically target at least several of the eleven structurally similar but functionally different HDAC isozymes, which hampers their broad usage in clinical settings. Selective inhibitors targeting single HDAC isozymes are being developed, but precise understanding in molecular terms of their selectivity remains sparse. Here, we show that HDAC8-selective inhibitors adopt a L-shaped conformation required for their binding to a HDAC8-specific pocket formed by HDAC8 catalytic tyrosine and HDAC8 L1 and L6 loops. In other HDAC isozymes, a L1-L6 lock sterically prevents L-shaped inhibitor binding. Shielding of the HDAC8-specific pocket by protein engineering decreases potency of HDAC8-selective inhibitors and affects catalytic activity. Collectively, our results unravel key HDAC8 active site structural and functional determinants important for the design of next-generation chemical probes and epigenetic drugs.
Characterization of histone deacetylase 8 (HDAC8) selective inhibition reveals specific active site structural and functional determinants.,Marek M, Shaik TB, Heimburg T, Chakrabarti A, Lancelot J, Ramos Morales E, Da Veiga C, Kalinin DV, Melesina J, Robaa D, Schmidtkunz K, Suzuki T, Holl R, Ennifar E, Pierce R, Jung M, Sippl W, Romier C J Med Chem. 2018 Oct 22. doi: 10.1021/acs.jmedchem.8b01087. PMID:30347148[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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:http://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
- ↑ Marek M, Shaik TB, Heimburg T, Chakrabarti A, Lancelot J, Ramos Morales E, Da Veiga C, Kalinin DV, Melesina J, Robaa D, Schmidtkunz K, Suzuki T, Holl R, Ennifar E, Pierce R, Jung M, Sippl W, Romier C. Characterization of histone deacetylase 8 (HDAC8) selective inhibition reveals specific active site structural and functional determinants. J Med Chem. 2018 Oct 22. doi: 10.1021/acs.jmedchem.8b01087. PMID:30347148 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b01087
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