User:Asif Hossain/Sandbox 1: Difference between revisions

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==HDAC8 Structure==

The crystal structure of human HDAC8 was determined using x-ray crystallography at a 2.0Å resolution. <ref name="Vannini, A., Volpari, C., Gallinari, P.">Vannini, A., Volpari, C., Gallinari, P., Jones, P., Mattu, M., Carfí, A., ... & Di Marco, S. (2007). Substrate binding to histone deacetylases as shown by the crystal structure of the HDAC8–substrate complex. EMBO reports, 8(9), 879-884. https://doi.org/10.1038/sj.embor.7401047 </ref> The structure includes two structural K ion and one catalytic Zn ion. HDAC8 is bound to a [https://en.wikipedia.org/wiki/P53 p-53] derived diacetylated peptide substrate as opposed to the natural histone substrate. This peptide includes a fluorescent coumarin ring likely used in past kinetic assays. The HDAC8 is made up of a <scene name='81/811084/Beta_sheets/6'>β-sheet</scene> with eight parallel β-strands located between 13 <scene name='81/811084/Alpha_helicesv2/4'>α-helices</scene>. The HDAC8 consists of 377 amino acids. <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 crystal structure of human HDAC8 was determined using x-ray crystallography at a 2.0Å resolution. <ref name="Vannini, A., Volpari, C., Gallinari, P.">Vannini, A., Volpari, C., Gallinari, P., Jones, P., Mattu, M., Carfí, A., ... & Di Marco, S. (2007). Substrate binding to histone deacetylases as shown by the crystal structure of the HDAC8–substrate complex. EMBO reports, 8(9), 879-884. https://doi.org/10.1038/sj.embor.7401047 </ref> The structure includes two structural K ion and one catalytic Zn ion. HDAC8 is bound to a [https://en.wikipedia.org/wiki/P53 p-53] <scene name='81/811084/Ligand/8'>derived diacetylated peptide substrate</scene> as opposed to the natural histone substrate. This peptide includes a fluorescent coumarin ring likely used in past kinetic assays. The HDAC8 is made up of a <scene name='81/811084/Beta_sheets/6'>β-sheet</scene> with eight parallel β-strands located between 13 <scene name='81/811084/Alpha_helicesv2/4'>α-helices</scene>. The HDAC8 consists of 377 amino acids. <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>

===Zinc Ion===

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By encasing the nonpolar, four-carbon side-chain of the Lys residue on the ligand, Phe152 and Phe208 engage in hydrophobic Van der Waals interactions with the ligand at different ends of the <scene name='81/811085/Binding_pocket_surface/3'>binding pocket</scene>. Trp141 and Met274 contribute to the overall shape through general hydrophobic interactions.<ref name="Whitehead">Whitehead, L., Dobler, M. R., Radetich, B., Zhu, Y., Atadja, P. W., Claiborne, T., ... & Shao, W. (2011). Human HDAC isoform selectivity achieved via exploitation of the acetate release channel with structurally unique small molecule inhibitors. Bioorganic & medicinal chemistry, 19(15), 4626-4634. https://doi.org/10.1016/j.bmc.2011.06.030 </ref> Finally, the carbonyl oxygen of <scene name='81/811085/Binding_pocket_glycine/2'>Gly151</scene> hydrogen bonds with the amide hydrogen of the acetylated lysine to further interact with the ligand in the relatively hydrophobic tunnel.<ref name="Vannini, A., Volpari, C., Gallinari, P.">Vannini, A., Volpari, C., Gallinari, P., Jones, P., Mattu, M., Carfí, A., ... & Di Marco, S. (2007). Substrate binding to histone deacetylases as shown by the crystal structure of the HDAC8–substrate complex. EMBO reports, 8(9), 879-884. https://doi.org/10.1038/sj.embor.7401047 </ref>

At the rim of the active site, <scene name='81/811084/Asp101/5'>Asp101</scene> is involved in two hydrogen bonds between its own carbonyl oxygens and two consecutive amide hydrogens of incoming ~~<scene name='81/811084/Ligand/8'>~~peptide derived ligand~~</scene>~~. This forces the ligand to assume a cis-conformation. In addition, extensive interactions among many other polar atoms near the rim of the active site help keep the ligand lodged in the hydrophobic tunnel.<ref name="Vannini, A., Volpari, C., Gallinari, P.">Vannini, A., Volpari, C., Gallinari, P., Jones, P., Mattu, M., Carfí, A., ... & Di Marco, S. (2007). Substrate binding to histone deacetylases as shown by the crystal structure of the HDAC8–substrate complex. EMBO reports, 8(9), 879-884. https://doi.org/10.1038/sj.embor.7401047 </ref>

At the rim of the active site, <scene name='81/811084/Asp101/5'>Asp101</scene> is involved in two hydrogen bonds between its own carbonyl oxygens and two consecutive amide hydrogens of incoming peptide derived ligand. This forces the ligand to assume a cis-conformation. In addition, extensive interactions among many other polar atoms near the rim of the active site help keep the ligand lodged in the hydrophobic tunnel.<ref name="Vannini, A., Volpari, C., Gallinari, P.">Vannini, A., Volpari, C., Gallinari, P., Jones, P., Mattu, M., Carfí, A., ... & Di Marco, S. (2007). Substrate binding to histone deacetylases as shown by the crystal structure of the HDAC8–substrate complex. EMBO reports, 8(9), 879-884. https://doi.org/10.1038/sj.embor.7401047 </ref>

===Additional Features===

@@ Line 13: / Line 13: @@
 ==HDAC8 Structure==
-The crystal structure of human HDAC8 was determined using x-ray crystallography at a 2.0Å resolution. <ref name="Vannini, A., Volpari, C., Gallinari, P.">Vannini, A., Volpari, C., Gallinari, P., Jones, P., Mattu, M., Carfí, A., ... & Di Marco, S. (2007). Substrate binding to histone deacetylases as shown by the crystal structure of the HDAC8–substrate complex. EMBO reports, 8(9), 879-884. https://doi.org/10.1038/sj.embor.7401047 </ref> The structure includes two structural K ion and one catalytic Zn ion. HDAC8 is bound to a [https://en.wikipedia.org/wiki/P53 p-53] derived diacetylated peptide substrate as opposed to the natural histone substrate. This peptide includes a fluorescent coumarin ring likely used in past kinetic assays. The HDAC8 is made up of a <scene name='81/811084/Beta_sheets/6'>β-sheet</scene> with eight parallel β-strands located between 13 <scene name='81/811084/Alpha_helicesv2/4'>α-helices</scene>. The HDAC8 consists of 377 amino acids.  <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 crystal structure of human HDAC8 was determined using x-ray crystallography at a 2.0Å resolution. <ref name="Vannini, A., Volpari, C., Gallinari, P.">Vannini, A., Volpari, C., Gallinari, P., Jones, P., Mattu, M., Carfí, A., ... & Di Marco, S. (2007). Substrate binding to histone deacetylases as shown by the crystal structure of the HDAC8–substrate complex. EMBO reports, 8(9), 879-884. https://doi.org/10.1038/sj.embor.7401047 </ref> The structure includes two structural K ion and one catalytic Zn ion. HDAC8 is bound to a [https://en.wikipedia.org/wiki/P53 p-53] <scene name='81/811084/Ligand/8'>derived diacetylated peptide substrate</scene> as opposed to the natural histone substrate. This peptide includes a fluorescent coumarin ring likely used in past kinetic assays. The HDAC8 is made up of a <scene name='81/811084/Beta_sheets/6'>β-sheet</scene> with eight parallel β-strands located between 13 <scene name='81/811084/Alpha_helicesv2/4'>α-helices</scene>. The HDAC8 consists of 377 amino acids.  <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>
 ===Zinc Ion===
@@ Line 24: / Line 24: @@
 By encasing the nonpolar, four-carbon side-chain of the Lys residue on the ligand, Phe152 and Phe208 engage in hydrophobic Van der Waals interactions with the ligand at different ends of the <scene name='81/811085/Binding_pocket_surface/3'>binding pocket</scene>. Trp141 and Met274 contribute to the overall shape through general hydrophobic interactions.<ref name="Whitehead">Whitehead, L., Dobler, M. R., Radetich, B., Zhu, Y., Atadja, P. W., Claiborne, T., ... & Shao, W. (2011). Human HDAC isoform selectivity achieved via exploitation of the acetate release channel with structurally unique small molecule inhibitors. Bioorganic & medicinal chemistry, 19(15), 4626-4634. https://doi.org/10.1016/j.bmc.2011.06.030 </ref> Finally, the carbonyl oxygen of <scene name='81/811085/Binding_pocket_glycine/2'>Gly151</scene> hydrogen bonds with the amide hydrogen of the acetylated lysine to further interact with the ligand in the relatively hydrophobic tunnel.<ref name="Vannini, A., Volpari, C., Gallinari, P.">Vannini, A., Volpari, C., Gallinari, P., Jones, P., Mattu, M., Carfí, A., ... & Di Marco, S. (2007). Substrate binding to histone deacetylases as shown by the crystal structure of the HDAC8–substrate complex. EMBO reports, 8(9), 879-884. https://doi.org/10.1038/sj.embor.7401047 </ref>
-At the rim of the active site, <scene name='81/811084/Asp101/5'>Asp101</scene> is involved in two hydrogen bonds between its own carbonyl oxygens and two consecutive amide hydrogens of incoming <scene name='81/811084/Ligand/8'>peptide derived ligand</scene>. This forces the ligand to assume a cis-conformation. In addition, extensive interactions among many other polar atoms near the rim of the active site help keep the ligand lodged in the hydrophobic tunnel.<ref name="Vannini, A., Volpari, C., Gallinari, P.">Vannini, A., Volpari, C., Gallinari, P., Jones, P., Mattu, M., Carfí, A., ... & Di Marco, S. (2007). Substrate binding to histone deacetylases as shown by the crystal structure of the HDAC8–substrate complex. EMBO reports, 8(9), 879-884. https://doi.org/10.1038/sj.embor.7401047 </ref>
+At the rim of the active site, <scene name='81/811084/Asp101/5'>Asp101</scene> is involved in two hydrogen bonds between its own carbonyl oxygens and two consecutive amide hydrogens of incoming peptide derived ligand. This forces the ligand to assume a cis-conformation. In addition, extensive interactions among many other polar atoms near the rim of the active site help keep the ligand lodged in the hydrophobic tunnel.<ref name="Vannini, A., Volpari, C., Gallinari, P.">Vannini, A., Volpari, C., Gallinari, P., Jones, P., Mattu, M., Carfí, A., ... & Di Marco, S. (2007). Substrate binding to histone deacetylases as shown by the crystal structure of the HDAC8–substrate complex. EMBO reports, 8(9), 879-884. https://doi.org/10.1038/sj.embor.7401047 </ref>
 ===Additional Features===