4qa5: Difference between revisions
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''' | ==Crystal structure of A188T/Y306F HDAC8 in complex with a tetrapeptide substrate== | ||
<StructureSection load='4qa5' size='340' side='right' caption='[[4qa5]], [[Resolution|resolution]] 1.76Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4qa5]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4QA5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4QA5 FirstGlance]. <br> | |||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=MCM:7-AMINO-4-METHYL-CHROMEN-2-ONE'>MCM</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene><br> | |||
<tr><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=ALY:N(6)-ACETYLLYSINE'>ALY</scene></td></tr> | |||
<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4qa0|4qa0]], [[4qa1|4qa1]], [[4qa2|4qa2]], [[4qa3|4qa3]], [[4qa4|4qa4]], [[4qa6|4qa6]], [[4qa7|4qa7]]</td></tr> | |||
<tr><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><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4qa5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qa5 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4qa5 RCSB], [http://www.ebi.ac.uk/pdbsum/4qa5 PDBsum]</span></td></tr> | |||
<table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Cornelia de Lange Syndrome (CdLS) is a multiple congenital anomaly disorder resulting from mutations in genes that encode the core components of the cohesin complex, SMC1A, SMC3, and RAD21, or two of its regulatory proteins, NIPBL and HDAC8. HDAC8 is the human SMC3 lysine deacetylase required for cohesin recycling in the cell cycle. To date, 16 different missense mutations in HDAC8 have recently been identified in children diagnosed with CdLS. To understand the molecular effects of these mutations in causing CdLS and overlapping phenotypes, we have fully characterized the structure and function of five HDAC8 mutants: C153F, A188T, I243N, T311M, and H334R. X-ray crystal structures reveal that each mutation causes local structural changes that compromise catalysis and/or thermostability. For example, the C153F mutation triggers conformational changes that block acetate product release channels, resulting in only 2% residual catalytic activity. In contrast, the H334R mutation causes structural changes in a polypeptide loop distant from the active site and results in 91% residual activity, but the thermostability of this mutant is significantly compromised. Strikingly, the catalytic activity of these mutants can be partially or fully rescued in vitro by the HDAC8 activator N-(phenylcarbamothioyl)benzamide. These results suggest that HDAC8 activators might be useful leads in the search for new therapeutic strategies in managing CdLS. | |||
Compromised Structure and Function of HDAC8 Mutants Identified in Cornelia de Lange Syndrome Spectrum Disorders.,Decroos C, Bowman CM, Moser JA, Christianson KE, Deardorff MA, Christianson DW ACS Chem Biol. 2014 Jul 30. PMID:25075551<ref>PMID:25075551</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Histone deacetylase]] | |||
[[Category: Bowman, C B.]] | |||
[[Category: Christianson, D W.]] | |||
[[Category: Christianson, K E.]] | |||
[[Category: Deardorff, M A.]] | |||
[[Category: Decroos, C.]] | |||
[[Category: Moser, J A.S.]] | |||
[[Category: Arginase/deacetylase fold]] | |||
[[Category: Cornelia de lange syndrome]] | |||
[[Category: Enzyme substrate complex]] | |||
[[Category: Histone deacetylase]] | |||
[[Category: Hydrolase]] | |||
[[Category: Metalloenzyme]] | |||