Loop Interactions and Dynamics Tune the Enzymatic Activity of the Human Histone Deacetylase 8
The human histone deacetylase 8 (HDAC8) is a key hydrolase in gene regulation and has been identified as a drug target for the treatment of several cancers. Previously the HDAC8 enzyme has been extensively studied using biochemical techniques, X-ray crystallography, and computational methods. Those...
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| Veröffentlicht in: | Journal of the American Chemical Society 2013-11, Vol.135 (47), p.17862-17868 |
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| container_issue | 47 |
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| container_title | Journal of the American Chemical Society |
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| creator | Kunze, Micha B. A Wright, David W Werbeck, Nicolas D Kirkpatrick, John Coveney, Peter V Hansen, D. Flemming |
| description | The human histone deacetylase 8 (HDAC8) is a key hydrolase in gene regulation and has been identified as a drug target for the treatment of several cancers. Previously the HDAC8 enzyme has been extensively studied using biochemical techniques, X-ray crystallography, and computational methods. Those investigations have yielded detailed information about the active site and have demonstrated that the substrate entrance surface is highly dynamic. Yet it has remained unclear how the dynamics of the entrance surface tune and influence the catalytic activity of HDAC8. Using long time scale all atom molecular dynamics simulations we have found a mechanism whereby the interactions and dynamics of two loops tune the configuration of functionally important residues of HDAC8 and could therefore influence the activity of the enzyme. We subsequently investigated this hypothesis using a well-established fluorescence activity assay and a noninvasive real-time progression assay, where deacetylation of a p53 based peptide was observed by nuclear magnetic resonance spectroscopy. Our work delivers detailed insight into the dynamic loop network of HDAC8 and provides an explanation for a number of experimental observations. |
| doi_str_mv | 10.1021/ja408184x |
| format | Article |
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Using long time scale all atom molecular dynamics simulations we have found a mechanism whereby the interactions and dynamics of two loops tune the configuration of functionally important residues of HDAC8 and could therefore influence the activity of the enzyme. We subsequently investigated this hypothesis using a well-established fluorescence activity assay and a noninvasive real-time progression assay, where deacetylation of a p53 based peptide was observed by nuclear magnetic resonance spectroscopy. 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Our work delivers detailed insight into the dynamic loop network of HDAC8 and provides an explanation for a number of experimental observations.</description><subject>Amino Acid Sequence</subject><subject>Assaying</subject><subject>Catalytic Domain</subject><subject>Crystallography, X-Ray</subject><subject>Dynamics</subject><subject>Entrances</subject><subject>Enzyme Activation</subject><subject>Enzymes</subject><subject>Histone Deacetylases - chemistry</subject><subject>Histone Deacetylases - genetics</subject><subject>Histone Deacetylases - metabolism</subject><subject>Histones</subject><subject>Human</subject><subject>Humans</subject><subject>Molecular Dynamics Simulation</subject><subject>Molecular Sequence Data</subject><subject>Mutation</subject><subject>Peptides</subject><subject>Protein Conformation</subject><subject>Repressor Proteins - chemistry</subject><subject>Repressor Proteins - genetics</subject><subject>Repressor Proteins - metabolism</subject><subject>Surface chemistry</subject><issn>0002-7863</issn><issn>1520-5126</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>N~.</sourceid><sourceid>EIF</sourceid><recordid>eNptkd1LHDEUxUOp1NX2of9AyUtBH8bmc5J5EcSvFRb6Yh9LuJtNapaZZJ1kxPGvd9rVRaFPl8v5ce7lHIS-UnJCCaM_1iCIplo8fkAzKhmpJGX1RzQjhLBK6Zrvo4Oc19MqmKaf0D4TVFEh1Qz9XqS0wTexuB5sCSlmDHGFL8YIXbAZ3w7R4XLn8GV8GjsoweKziXsIZcTJ_1PmQwcRz0MuaWIvHFhXxhayw_oz2vPQZvflZR6iX1eXt-fzavHz-ub8bFGB4LpUKyKVENZTv2pq75y0kgJhHrznS6XdkirileJMeqm9B6ItXzYNA99I7oDxQ3S69d0My86trIulh9Zs-tBBP5oEwbxXYrgzf9KD4Q2rFRGTwdGLQZ_uB5eL6UK2rm0hujRkQ5XkQnNe6wk93qK2Tzn3zu_OUGL-1mF2dUzst7d_7cjX_Cfg-xYAm806DX2cYvqP0TNbmpMn</recordid><startdate>20131127</startdate><enddate>20131127</enddate><creator>Kunze, Micha B. 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Flemming</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a438t-d05744cf1fd96fee5c51a02faff3b78eb170f77325f58ffa08c3b992af953ea23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Amino Acid Sequence</topic><topic>Assaying</topic><topic>Catalytic Domain</topic><topic>Crystallography, X-Ray</topic><topic>Dynamics</topic><topic>Entrances</topic><topic>Enzyme Activation</topic><topic>Enzymes</topic><topic>Histone Deacetylases - chemistry</topic><topic>Histone Deacetylases - genetics</topic><topic>Histone Deacetylases - metabolism</topic><topic>Histones</topic><topic>Human</topic><topic>Humans</topic><topic>Molecular Dynamics Simulation</topic><topic>Molecular Sequence Data</topic><topic>Mutation</topic><topic>Peptides</topic><topic>Protein Conformation</topic><topic>Repressor Proteins - chemistry</topic><topic>Repressor Proteins - genetics</topic><topic>Repressor Proteins - metabolism</topic><topic>Surface chemistry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kunze, Micha B. 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Yet it has remained unclear how the dynamics of the entrance surface tune and influence the catalytic activity of HDAC8. Using long time scale all atom molecular dynamics simulations we have found a mechanism whereby the interactions and dynamics of two loops tune the configuration of functionally important residues of HDAC8 and could therefore influence the activity of the enzyme. We subsequently investigated this hypothesis using a well-established fluorescence activity assay and a noninvasive real-time progression assay, where deacetylation of a p53 based peptide was observed by nuclear magnetic resonance spectroscopy. Our work delivers detailed insight into the dynamic loop network of HDAC8 and provides an explanation for a number of experimental observations.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>24171457</pmid><doi>10.1021/ja408184x</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Amino Acid Sequence Assaying Catalytic Domain Crystallography, X-Ray Dynamics Entrances Enzyme Activation Enzymes Histone Deacetylases - chemistry Histone Deacetylases - genetics Histone Deacetylases - metabolism Histones Human Humans Molecular Dynamics Simulation Molecular Sequence Data Mutation Peptides Protein Conformation Repressor Proteins - chemistry Repressor Proteins - genetics Repressor Proteins - metabolism Surface chemistry |
| title | Loop Interactions and Dynamics Tune the Enzymatic Activity of the Human Histone Deacetylase 8 |
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