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You may include any references to papers as in: the use of JSmol in Proteopedia [1] or to the article describing Jmol [2] to the rescue.
Introduction
Histones
Histones are a family of basic, positively charged proteins that associate with DNA inside the nucleus to help condense the DNA into chromatin [3]. The nuclear DNA is wrapped around the histone in order to fit in the nucleus. Nucleosomes are chromatin beads made up of DNA wrapped around eight histone proteins, or a histone octamer [3]. The modification of histones are a type of epigenetics, where changes are made in gene expression without altering the DNA sequence. Four different examples of modifying histones including Histone acetylation, Histone deacetylation, Histone methylation and Histone demethylation [3].
Histone Deacetylases (HDACs)
ε-Amino-lysine acetylation is a type of histone modification that controls the stability of proteins and biological function in eukaryotic cells [4]. Histone Deacetylation is the reversal process for this acetylation modification. There are different classes of HDACs based on phylogenetic analysis:
•Class I - HDACs 1-3 and 8, which are homologous to yeast Rpd3
•Class II - HDACs 4-7, 9 and 10, which are homologous to yeast Hda1
•Class III - Sirtuin deacetylases
•Class IV - HDAC 11 [4].
HDACs 1-11 are metalloenzymes and require a zinc ion for deacetylation [4].
HDAC8
Histone Deacetylase 8 is an enzyme found in Homo sapiens. HDAC8 is 388 residues long and consists of eight-stranded parallel β-sheets surrounded by 11 α-helices [4]. HDAC8 is the only functional HDAC that is found to be a single polypeptide instead of being high-molecular-weight multi-protein complexes [4]. The substrate bound to the HDAC8 includes an acetyl group, one arginine, one histidine, two lysines and MCM, a Coumarin fluorescence tag.
Structure
General Structure Information
Inhibitor
Potassium Binding Site
There are two potassium ions in HDAC8. While their exact function is unknown, these ions do increase the catalytic activity and stability of the enzyme overall. The potassium ion closest to the active site becomes a . This potassium ion octahedrally coordinates with the side chain oxygen of S199 and D176 and the backbone oxygen of D176, D178, H180 and L200 [5]. Because the second potassium ion is about 20 Å from the catalytic center, this only regulates the enzymatic activity by an allosteric effect [5].
Deacetylation
Figure 1. Deacetylation by HDAC8
Active Site
Substrates are deacetylated via a 2+ metal ion mechanism. The Zinc ion by withdrawing electron density from the water due to the positive charge, making the water more acidic and a better nucleophile.
Disease
HDACis
References
- ↑ Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:http://dx.doi.org/10.1002/ijch.201300024
- ↑ Herraez A. Biomolecules in the computer: Jmol to the rescue. Biochem Mol Biol Educ. 2006 Jul;34(4):255-61. doi: 10.1002/bmb.2006.494034042644. PMID:21638687 doi:10.1002/bmb.2006.494034042644
- ↑ 3.0 3.1 3.2 Histones | Learn Science at Scitable https://www.nature.com/scitable/definition/histone-histones-57
- ↑ 4.0 4.1 4.2 4.3 4.4 Vannini A, Volpari C, Gallinari P, Jones P, Mattu M, Carfi A, De Francesco R, Steinkuhler C, Di Marco S. Substrate binding to histone deacetylases as shown by the crystal structure of the HDAC8-substrate complex. EMBO Rep. 2007 Sep;8(9):879-84. Epub 2007 Aug 10. PMID:17721440
- ↑ 5.0 5.1 Chen K, Zhang X, Wu YD, Wiest O. Inhibition and mechanism of HDAC8 revisited. J Am Chem Soc. 2014 Aug 20;136(33):11636-43. doi: 10.1021/ja501548p. Epub 2014, Aug 7. PMID:25060069 doi:http://dx.doi.org/10.1021/ja501548p
Student Contributors
- Courtney Brown
- Cassandra Marsh
- Carolyn Hurdle
