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===Additional Features===
===Additional Features===
There are two potassium ions bound in the HDAC8 structure. Site 1 is close to the zinc-binding site with 7Å while site 2 lies toward the periphery of the HDAC8.<ref name="Vannini, A., Volpari, C., Filocamo, G.">Vannini, A., Volpari, C., Filocamo, G., Casavola, E. C., Brunetti, M., Renzoni, D., ... & Steinkühler, C. (2004). Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor. Proceedings of the National Academy of Sciences, 101(42), 15064-15069. https://dx.doi.org/10.1073%2Fpnas.0404603101</ref> Site 1 is of interest to the active site of HDAC8 as it is coordinated by the main chain carbonyl oxygens of Asp178 and His180 whose side chains are important in zinc chelation. Furthermore, the potassium ion increases the positive electrostatic potential in the active site and this could help stabilize the oxyanion hole formed in the transition state.<ref name="Vannini, A., Volpari, C., Filocamo, G.">Vannini, A., Volpari, C., Filocamo, G., Casavola, E. C., Brunetti, M., Renzoni, D., ... & Steinkühler, C. (2004). Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor. Proceedings of the National Academy of Sciences, 101(42), 15064-15069. https://dx.doi.org/10.1073%2Fpnas.0404603101</ref>
There are two potassium ions bound in the HDAC8 structure. Potassium 1 is 7Å away from the active site while potassium 2 lies toward the exterior of the HDAC8.<ref name="Vannini, A., Volpari, C., Filocamo, G.">Vannini, A., Volpari, C., Filocamo, G., Casavola, E. C., Brunetti, M., Renzoni, D., ... & Steinkühler, C. (2004). Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor. Proceedings of the National Academy of Sciences, 101(42), 15064-15069. https://dx.doi.org/10.1073%2Fpnas.0404603101</ref>. It is suggested that potassium 1 is of interest to the active site of HDAC8 because it is tethered to the enzyme by the main chain carbonyl oxygens of Asp178 and His180 which stabilizes the Zn<sup>2+</sup> in the active site. Furthermore, the potassium ion increases the positive charge in the active site and this could help stabilize the oxyanion hole that is formed in the transition state.<ref name="Vannini, A., Volpari, C., Filocamo, G.">Vannini, A., Volpari, C., Filocamo, G., Casavola, E. C., Brunetti, M., Renzoni, D., ... & Steinkühler, C. (2004). Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor. Proceedings of the National Academy of Sciences, 101(42), 15064-15069. https://dx.doi.org/10.1073%2Fpnas.0404603101</ref>
   
   
<scene name='81/811087/Active_site_loop_1_s30-k36/11'>N-Terminus L1 loop </scene>(amino acid residues 30-36) lines a large part of one face of the active site pocket and extends to the protein surface. This results in a larger surface opening of the active site pocket. It is suggested that this loop has high flexibility that enables HDAC8 to more efficiently accommodate binding to a variety of different ligands. <ref name="Somoza">Somoza J, Skene R. Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases. Structure, 12(7), 1325-1334.2004. https://doi.org/10.1016/j.str.2004.04.012 </ref>
<scene name='81/811087/Active_site_loop_1_s30-k36/11'>N-Terminus L1 loop </scene>(amino acid residues 30-36) makes up a significant part of the active site pocket. It is suggested that this loop has high flexibility that enables HDAC8 to more efficiently adjust binding to different ligands. <ref name="Somoza">Somoza J, Skene R. Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases. Structure, 12(7), 1325-1334.2004. https://doi.org/10.1016/j.str.2004.04.012 </ref>


The activity of HDAC8 is regulated by phosphorylation at <scene name='81/811087/Active_site_loop_1_s30-k36/12'>Ser39</scene> by [https://en.wikipedia.org/wiki/Protein_kinase_A protein kinase A(PKA)] as the phosphorylation has been shown to decrease the enzyme’s activity.<ref name="Somoza">Somoza J, Skene R. Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases. Structure, 12(7), 1325-1334.2004. https://doi.org/10.1016/j.str.2004.04.012 </ref> Ser39 lies at the surface of HDAC8, approximately 20Å from the opening to the HDAC8 active site so it is likely part of the surface that interacts with the target histone. The interaction between the HDAC8 and target histone could be disrupted by the phosphorylation of Ser39 because the phosphorylated Ser39 elicits a structural rearrangement that extends to the active site and thus disrupts enzyme activity. Ser39 elicits this rearrangement by interactions with structural elements in the conformational active loop L1, such as Lys36. Therefore, the Ser39 phosphorylation by PKA is likely inducing a conformational change of the L1 loop that prohibits a competent substrate binding.<ref name="Somoza">Somoza J, Skene R. Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases. Structure, 12(7), 1325-1334.2004. https://doi.org/10.1016/j.str.2004.04.012 </ref>
The activity of HDAC8 is regulated by phosphorylation at <scene name='81/811087/Active_site_loop_1_s30-k36/12'>Ser39</scene> by [https://en.wikipedia.org/wiki/Protein_kinase_A protein kinase A(PKA)] as the phosphorylation has been shown to decrease the enzyme’s activity.<ref name="Somoza">Somoza J, Skene R. Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases. Structure, 12(7), 1325-1334.2004. https://doi.org/10.1016/j.str.2004.04.012 </ref> Ser39 lies at the surface of HDAC8, approximately 20Å from the opening to the HDAC8 active site so it is likely part of the surface that interacts with the target histone. The interaction between the HDAC8 and target histone could be disrupted by the phosphorylation of Ser39 because the phosphorylated Ser39 elicits a structural rearrangement that extends to the active site and thus disrupts enzyme activity. Ser39 elicits this rearrangement by interactions with structural elements in the conformational active loop L1, such as Lys36. Therefore, the Ser39 phosphorylation by PKA is likely inducing a conformational change of the L1 loop that prohibits a competent substrate binding.<ref name="Somoza">Somoza J, Skene R. Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases. Structure, 12(7), 1325-1334.2004. https://doi.org/10.1016/j.str.2004.04.012 </ref>
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