User:Asif Hossain/Sandbox 1: Difference between revisions

There are two <scene name='81/811085/Overall_structure/8'>potassium ions</scene> 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 <scene name='81/811085/Potassium_ion/2'>Asp178 and His180</scene> which stabilizes the Zn²⁺ 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>

   

The activity of HDAC8 is regulated by phosphorylation at <scene name='81/811087/Active_site_loop_1_s30-k36/13'>Ser39</scene> by [https://en.wikipedia.org/wiki/Protein_kinase_A protein kinase A (PKA)] as the phosphorylation has been shown to decrease the activity of HDAC8.<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> It is suggested that the phosphorylation of Ser39 can interfere with the interaction between HDAC8 and the target histone because Ser39 is at the periphery of HDAC8, approximately 20Å from the active site. The interaction is disrupted because the phosphorylated Ser39 elicits a structural rearrangement that reaches the active site and disrupts enzyme activity. Ser39 elicits the 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 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>