6hoy

From Proteopedia

(Difference between revisions)

Revision as of 07:58, 24 April 2019

Human Sirt6 in complex with ADP-ribose and the inhibitor trichostatin A

Structural highlights

6hoy is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , , , ,
Gene:	SIRT6, SIR2L6 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[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.^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

Protein lysine deacylases comprise three zinc-dependent families and the NAD+-dependent Sirtuins Sirt1-7, which contribute to aging-related diseases. Few Sirt6-specific inhibitors are available. Trichostatin A, which belongs to the potent, zinc-chelating hydroxamate inhibitors of zinc-dependent deacylases, was recently found to potently and iso-form-specifically inhibit Sirt6. We solved a crystal structure of a Sirt6/ADP-ribose/trichostatin A complex, which reveals nicotinamide pocket and acyl channel as binding site and provides interaction details supporting the develop-ment of improved deacylase inhibitors.

Structural basis of Sirtuin 6 inhibition by the hydroxamate trichostatin A - implications for protein deacylase drug development.,You W, Steegborn C J Med Chem. 2018 Nov 5. doi: 10.1021/acs.jmedchem.8b01455. PMID:30395713^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Michishita E, McCord RA, Berber E, Kioi M, Padilla-Nash H, Damian M, Cheung P, Kusumoto R, Kawahara TL, Barrett JC, Chang HY, Bohr VA, Ried T, Gozani O, Chua KF. SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature. 2008 Mar 27;452(7186):492-6. doi: 10.1038/nature06736. Epub 2008 Mar 12. PMID:18337721 doi:10.1038/nature06736
↑ Kawahara TL, Michishita E, Adler AS, Damian M, Berber E, Lin M, McCord RA, Ongaigui KC, Boxer LD, Chang HY, Chua KF. SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span. Cell. 2009 Jan 9;136(1):62-74. doi: 10.1016/j.cell.2008.10.052. PMID:19135889 doi:10.1016/j.cell.2008.10.052
↑ Michishita E, McCord RA, Boxer LD, Barber MF, Hong T, Gozani O, Chua KF. Cell cycle-dependent deacetylation of telomeric histone H3 lysine K56 by human SIRT6. Cell Cycle. 2009 Aug 15;8(16):2664-6. Epub 2009 Aug 26. PMID:19625767
↑ Kaidi A, Weinert BT, Choudhary C, Jackson SP. Human SIRT6 promotes DNA end resection through CtIP deacetylation. Science. 2010 Sep 10;329(5997):1348-53. doi: 10.1126/science.1192049. PMID:20829486 doi:10.1126/science.1192049
↑ Pan PW, Feldman JL, Devries MK, Dong A, Edwards AM, Denu JM. Structure and biochemical functions of SIRT6. J Biol Chem. 2011 Apr 22;286(16):14575-87. Epub 2011 Mar 1. PMID:21362626 doi:10.1074/jbc.M111.218990
↑ You W, Steegborn C. Structural basis of Sirtuin 6 inhibition by the hydroxamate trichostatin A - implications for protein deacylase drug development. J Med Chem. 2018 Nov 5. doi: 10.1021/acs.jmedchem.8b01455. PMID:30395713 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b01455

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6hoy"

@@ Line 1: / Line 1: @@
 ==Human Sirt6 in complex with ADP-ribose and the inhibitor trichostatin A==
-<StructureSection load='6hoy' size='340' side='right' caption='[[6hoy]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
+<StructureSection load='6hoy' size='340' side='right'caption='[[6hoy]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6hoy]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6HOY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6HOY FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6hoy]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6HOY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6HOY FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AR6:[(2R,3S,4R,5R)-5-(6-AMINOPURIN-9-YL)-3,4-DIHYDROXY-OXOLAN-2-YL]METHYL+[HYDROXY-[[(2R,3S,4R,5S)-3,4,5-TRIHYDROXYOXOLAN-2-YL]METHOXY]PHOSPHORYL]+HYDROGEN+PHOSPHATE'>AR6</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=TSN:TRICHOSTATIN+A'>TSN</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SIRT6, SIR2L6 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6hoy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6hoy OCA], [http://pdbe.org/6hoy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6hoy RCSB], [http://www.ebi.ac.uk/pdbsum/6hoy PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6hoy ProSAT]</span></td></tr>
 </table>
@@ Line 22: / Line 23: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Steegborn, C]]
 [[Category: You, W]]

6hoy

From Proteopedia

Revision as of 07:58, 24 April 2019

Human Sirt6 in complex with ADP-ribose and the inhibitor trichostatin A

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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