5dc5
From Proteopedia
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| - | ''' | + | ==Crystal structure of D176N HDAC8 in complex with M344== |
| + | <StructureSection load='5dc5' size='340' side='right' caption='[[5dc5]], [[Resolution|resolution]] 1.94Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5dc5]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5DC5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5DC5 FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=B3N:4-(DIMETHYLAMINO)-N-[7-(HYDROXYAMINO)-7-OXOHEPTYL]BENZAMIDE'>B3N</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | ||
| + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5dc6|5dc6]], [[5dc7|5dc7]], [[5dc8|5dc8]]</td></tr> | ||
| + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Histone_deacetylase Histone deacetylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.1.98 3.5.1.98] </span></td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5dc5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dc5 OCA], [http://pdbe.org/5dc5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5dc5 RCSB], [http://www.ebi.ac.uk/pdbsum/5dc5 PDBsum]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/HDAC8_HUMAN HDAC8_HUMAN]] Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. May play a role in smooth muscle cell contractility.<ref>PMID:10748112</ref> <ref>PMID:10926844</ref> <ref>PMID:10922473</ref> <ref>PMID:14701748</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Histone deacetylases (HDACs) regulate cellular processes such as differentiation and apoptosis and are targeted by anticancer therapeutics in development and in the clinic. HDAC8 is a metal-dependent class I HDAC and is proposed to use a general acid-base catalytic pair in the mechanism of amide bond hydrolysis. Here, we report site-directed mutagenesis and enzymological measurements to elucidate the catalytic mechanism of HDAC8. Specifically, we focus on the catalytic function of Y306 and the histidine-aspartate dyads H142-D176 and H143-D183. Additionally, we report X-ray crystal structures of four representative HDAC8 mutants: D176N, D176N/Y306F, D176A/Y306F, and H142A/Y306F. These structures provide a useful framework for understanding enzymological measurements. The pH dependence of kcat/KM for wild-type Co(II)-HDAC8 is bell-shaped with two pKa values of 7.4 and 10.0. The upper pKa reflects the ionization of the metal-bound water molecule and shifts to 9.1 in Zn(II)-HDAC8. The H142A mutant has activity 230-fold lower than that of wild-type HDAC8, but the pKa1 value is not altered. Y306F HDAC8 is 150-fold less active than the wild-type enzyme; crystal structures show that Y306 hydrogen bonds with the zinc-bound substrate carbonyl, poised for transition state stabilization. The H143A and H142A/H143A mutants exhibit activity that is >80000-fold lower than that of wild-type HDAC8; the buried D176N and D176A mutants have significant catalytic effects, with more subtle effects caused by D183N and D183A. These enzymological and structural studies strongly suggest that H143 functions as a single general base-general acid catalyst, while H142 remains positively charged and serves as an electrostatic catalyst for transition state stabilization. | ||
| - | + | General Base-General Acid Catalysis in Human Histone Deacetylase 8.,Gantt SM Fsgm, Decroos C, Lee MS, Gullett LE, Bowman CM, Christianson DW, Fierke CA Biochemistry. 2016 Jan 25. PMID:26806311<ref>PMID:26806311</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | <div class="pdbe-citations 5dc5" style="background-color:#fffaf0;"></div> | |
| - | [[Category: | + | == References == |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Histone deacetylase]] | ||
| + | [[Category: Christianson, D W]] | ||
[[Category: Decroos, C]] | [[Category: Decroos, C]] | ||
| - | [[Category: Lee, M | + | [[Category: Lee, M S]] |
| - | [[Category: | + | [[Category: Arginase fold]] |
| + | [[Category: Deacetylase]] | ||
| + | [[Category: Enzyme-inhibitor complex]] | ||
| + | [[Category: Histone deacetylase 8]] | ||
| + | [[Category: Hydrolase-hydrloase inhibitor complex]] | ||
Revision as of 15:44, 3 February 2016
Crystal structure of D176N HDAC8 in complex with M344
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