5mgn

From Proteopedia

(Difference between revisions)

Current revision

Human Sirt6 in complex with activator UBCS38

Structural highlights

5mgn is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.07Å
Ligands:	, , , ,
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

Sirtuins are protein deacylases regulating metabolism and stress responses, and are implicated in aging-related diseases. Small molecule activators for the human sirtuins Sirt1-7 are sought as chemical tools and potential therapeutics, such as for cancer. Activators are available for Sirt1 and exploit its unique N-terminus, whereas drug-like activators for Sirt2-7 are lacking. We synthesized and screened pyrrolo[1,2-a]quinoxaline derivatives, yielding the first synthetic Sirt6 activators. Biochemical assays show direct, substrate-independent compound binding to the Sirt6 catalytic core and potent activation of Sirt6-dependent deacetylation of peptide substrates and complete nucleosomes. Crystal structures of Sirt6/activator complexes reveal that the compounds bind to a Sirt6-specific acyl channel pocket and identify key interactions. Our results establish potent Sirt6 activation with small molecules and provide a structural basis for further development of Sirt6 activators as tools and therapeutics.

Structural Basis of Sirtuin 6 Activation by Synthetic Small Molecules.,You W, Rotili D, Li TM, Kambach C, Meleshin M, Schutkowski M, Chua KF, Mai A, Steegborn C Angew Chem Int Ed Engl. 2016 Dec 19. doi: 10.1002/anie.201610082. PMID:27990725^[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, Rotili D, Li TM, Kambach C, Meleshin M, Schutkowski M, Chua KF, Mai A, Steegborn C. Structural Basis of Sirtuin 6 Activation by Synthetic Small Molecules. Angew Chem Int Ed Engl. 2016 Dec 19. doi: 10.1002/anie.201610082. PMID:27990725 doi:http://dx.doi.org/10.1002/anie.201610082

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5mgn"

Categories: Homo sapiens | Large Structures | Kambach C | Steegborn C | You W

@@ Line 1: / Line 1: @@
 ==Human Sirt6 in complex with activator UBCS38==
-<StructureSection load='5mgn' size='340' side='right' caption='[[5mgn]], [[Resolution|resolution]] 2.07&Aring;' scene=''>
+<StructureSection load='5mgn' size='340' side='right'caption='[[5mgn]], [[Resolution|resolution]] 2.07&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5mgn]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MGN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5MGN FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5mgn]] is a 2 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=5MGN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5MGN FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7N2:(4~{R})-4-PYRIDIN-3-YL-5-[3-(TRIFLUOROMETHYL)PHENYL]SULFONYL-4~{H}-PYRROLO[1,2-A]QUINOXALINE'>7N2</scene>, <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=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.07&#8491;</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=5mgn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mgn OCA], [http://pdbe.org/5mgn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mgn RCSB], [http://www.ebi.ac.uk/pdbsum/5mgn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mgn ProSAT]</span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7N2:(4~{R})-4-PYRIDIN-3-YL-5-[3-(TRIFLUOROMETHYL)PHENYL]SULFONYL-4~{H}-PYRROLO[1,2-A]QUINOXALINE'>7N2</scene>, <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=SO4:SULFATE+ION'>SO4</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=5mgn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mgn OCA], [https://pdbe.org/5mgn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5mgn RCSB], [https://www.ebi.ac.uk/pdbsum/5mgn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5mgn ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://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>
+[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 ==
@@ Line 18: / Line 19: @@
 </div>
 <div class="pdbe-citations 5mgn" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Histone deacetylase 3D structures|Histone deacetylase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Kambach, C]]
+[[Category: Homo sapiens]]
-[[Category: Steegborn, C]]
+[[Category: Large Structures]]
-[[Category: You, W]]
+[[Category: Kambach C]]
-[[Category: Drug]]
+[[Category: Steegborn C]]
-[[Category: Hydrolase]]
+[[Category: You W]]

5mgn

From Proteopedia

Current revision

Human Sirt6 in complex with activator UBCS38

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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