View source for 3pkj


==Human SIRT6 crystal structure in complex with 2'-N-Acetyl ADP ribose==
<StructureSection load='3pkj' size='340' side='right'caption='[[3pkj]], [[Resolution|resolution]] 2.12&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3pkj]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3PKJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3PKJ FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.12&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A2N:[(2R,3S,4R,5R)-4-(ACETYLAMINO)-3,5-DIHYDROXYTETRAHYDROFURAN-2-YL]METHYL+[(2R,3S,4R,5R)-5-(6-AMINO-9H-PURIN-9-YL)-3,4-DIHYDROXYTETRAHYDROFURAN-2-YL]METHYL+DIHYDROGEN+DIPHOSPHATE'>A2N</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3pkj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3pkj OCA], [https://pdbe.org/3pkj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3pkj RCSB], [https://www.ebi.ac.uk/pdbsum/3pkj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3pkj ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/SIR6_HUMAN SIR6_HUMAN] NAD-dependent protein deacetylase. Has deacetylase activity towards histone H3K9Ac and H3K56Ac. Modulates acetylation of histone H3 in telomeric chromatin during the S-phase of the cell cycle. Deacetylates histone H3K9Ac at NF-kappa-B target promoters and may down-regulate the expression of a subset of NF-kappa-B target genes. Acts as a corepressor of the transcription factor HIF1A to control the expression of multiple glycolytic genes to regulate glucose homeostasis. Required for genomic stability. Regulates the production of TNF protein. Has a role in the regulation of life span (By similarity). Deacetylation of nucleosomes interferes with RELA binding to target DNA. May be required for the association of WRN with telomeres during S-phase and for normal telomere maintenance. Required for genomic stability. Required for normal IGF1 serum levels and normal glucose homeostasis. Modulates cellular senescence and apoptosis. On DNA damage, promotes DNA end resection via deacetylation of RBBP8. Has very weak deacetylase activity and can bind NAD(+) in the absence of acetylated substrate.<ref>PMID:18337721</ref> <ref>PMID:19135889</ref> <ref>PMID:19625767</ref> <ref>PMID:20829486</ref> <ref>PMID:21362626</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
SIRT6 is a member of the evolutionarily conserved sirtuin family of NAD(+)-dependent protein deacetylases and functions in genomic stability and transcriptional control of glucose metabolism. Early reports suggested that SIRT6 performs ADP-ribosylation, whereas more recent studies have suggested that SIRT6 functions mainly as a histone deacetylase. Thus, the molecular functions of SIRT6 remain uncertain. Here, we perform biochemical, kinetic, and structural studies to provide new mechanistic insight into the functions of SIRT6. Utilizing three different assays, we provide biochemical and kinetic evidence that SIRT6-dependent histone deacetylation produces O-acetyl-ADP-ribose but at a rate approximately 1,000 times slower than other highly active sirtuins. To understand the molecular basis for such low deacetylase activity, we solved the first crystal structures of this class IV sirtuin in complex with ADP-ribose and the non-hydrolyzable analog of O-acetyl-ADP-ribose, 2'-N-acetyl-ADP-ribose. The structures revealed unique features of human SIRT6, including a splayed zinc-binding domain and the absence of a helix bundle that in other sirtuin structures connects the zinc-binding motif and Rossmann fold domain. SIRT6 also lacks the conserved, highly flexible, NAD(+)-binding loop and instead contains a stable single helix. These differences led us to hypothesize that SIRT6, unlike all other studied sirtuins, would be able to bind NAD(+) in the absence of an acetylated substrate. Indeed, we found that SIRT6 binds NAD(+) with relatively high affinity (K(d) = 27 +/- 1 muM) in the absence of an acetylated substrate. Isothermal titration calorimetry and tryptophan fluorescence binding assays suggested that ADP-ribose and NAD(+) induce different structural perturbations and that NADH does not bind to SIRT6. Collectively, these new insights imply a unique activating mechanism and/or the possibility that SIRT6 could act as an NAD(+) metabolite sensor.

Structure and biochemical functions of SIRT6.,Pan PW, Feldman JL, Devries MK, Dong A, Edwards AM, Denu JM J Biol Chem. 2011 Apr 22;286(16):14575-87. Epub 2011 Mar 1. PMID:21362626<ref>PMID:21362626</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 3pkj" style="background-color:#fffaf0;"></div>

==See Also==
*[[Histone deacetylase 3D structures|Histone deacetylase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Arrowsmith CH]]
[[Category: Bountra C]]
[[Category: Dong A]]
[[Category: Edwards AM]]
[[Category: Loppnau P]]
[[Category: Min J]]
[[Category: Pan PW]]
[[Category: Qiu W]]
[[Category: Ravichandran M]]
[[Category: Walker JR]]
[[Category: Wang J]]
[[Category: Weigelt J]]