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4bn4

From Proteopedia

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Current revision

Structure of human SIRT3 in complex with ADP-ribose

Structural highlights

4bn4 is a 1 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 1.3Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

SIR3_HUMAN NAD-dependent protein deacetylase. Activates mitochondrial target proteins, including ACSS1, IDH2 and GDH by deacetylating key lysine residues. Contributes to the regulation of the cellular energy metabolism. Important for regulating tissue-specific ATP levels.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Sirtuins are NAD(+)-dependent protein deacetylases that regulate metabolism and aging processes and are considered to be attractive therapeutic targets. Most available sirtuin modulators are little understood mechanistically, hindering their improvement. SRT1720 was initially described as an activator of human Sirt1, but it also potently inhibits human Sirt3. Here, the molecular mechanism of the inhibition of Sirt3 by SRT1720 is described. A crystal structure of Sirt3 in complex with SRT1720 and an NAD(+) analogue reveals that the compound partially occupies the acetyl-Lys binding site, thus explaining the reported competition with the peptide substrate. The compound packs against a hydrophobic protein patch and binds with its opposite surface to the NAD(+) nicotinamide, resulting in an exceptionally tight sandwich-like interaction. The observed arrangement rationalizes the uncompetitive inhibition with NAD(+), and binding measurements confirm that the nicotinamide moiety of NAD(+) supports inhibitor binding. Consistently, no inhibitor is bound in a second crystal structure of Sirt3 that was solved complexed with ADP-ribose and crystallized in the presence of SRT1720. These results reveal a novel sirtuin inhibitor binding site and mechanism, and provide a structural basis for compound improvement.

Structures of human sirtuin 3 complexes with ADP-ribose and with carba-NAD(+) and SRT1720: binding details and inhibition mechanism.,Nguyen GT, Schaefer S, Gertz M, Weyand M, Steegborn C Acta Crystallogr D Biol Crystallogr. 2013 Aug;69(Pt 8):1423-32. doi:, 10.1107/S0907444913015448. Epub 2013 Jul 17. PMID:23897466^[5]

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

References

↑ Schwer B, Bunkenborg J, Verdin RO, Andersen JS, Verdin E. Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2. Proc Natl Acad Sci U S A. 2006 Jul 5;103(27):10224-9. Epub 2006 Jun 20. PMID:16788062 doi:10.1073/pnas.0603968103
↑ Schlicker C, Gertz M, Papatheodorou P, Kachholz B, Becker CF, Steegborn C. Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5. J Mol Biol. 2008 Oct 10;382(3):790-801. doi: 10.1016/j.jmb.2008.07.048. Epub 2008, Jul 25. PMID:18680753 doi:10.1016/j.jmb.2008.07.048
↑ Ahn BH, Kim HS, Song S, Lee IH, Liu J, Vassilopoulos A, Deng CX, Finkel T. A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14447-52. doi:, 10.1073/pnas.0803790105. Epub 2008 Sep 15. PMID:18794531 doi:10.1073/pnas.0803790105
↑ Jin L, Wei W, Jiang Y, Peng H, Cai J, Mao C, Dai H, Choy W, Bemis JE, Jirousek MR, Milne JC, Westphal CH, Perni RB. Crystal structures of human SIRT3 displaying substrate-induced conformational changes. J Biol Chem. 2009 Sep 4;284(36):24394-405. Epub 2009 Jun 16. PMID:19535340 doi:10.1074/jbc.M109.014928
↑ Nguyen GT, Schaefer S, Gertz M, Weyand M, Steegborn C. Structures of human sirtuin 3 complexes with ADP-ribose and with carba-NAD(+) and SRT1720: binding details and inhibition mechanism. Acta Crystallogr D Biol Crystallogr. 2013 Aug;69(Pt 8):1423-32. doi:, 10.1107/S0907444913015448. Epub 2013 Jul 17. PMID:23897466 doi:10.1107/S0907444913015448

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/4bn4"

@@ Line 1: / Line 1: @@
 ==Structure of human SIRT3 in complex with ADP-ribose==
-<StructureSection load='4bn4' size='340' side='right' caption='[[4bn4]], [[Resolution|resolution]] 1.30&Aring;' scene=''>
+<StructureSection load='4bn4' size='340' side='right'caption='[[4bn4]], [[Resolution|resolution]] 1.30&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4bn4]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BN4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BN4 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4bn4]] is a 1 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=4BN4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BN4 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=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=OP2:2-[2-[2-[2-[2-(2-HYDROXYETHYLOXY)ETHOXY]ETHOXY]ETHOXY]ETHOXY]ETHANOIC+ACID'>OP2</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]] 1.3&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4bn5|4bn5]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=OP2:2-[2-[2-[2-[2-(2-HYDROXYETHYLOXY)ETHOXY]ETHOXY]ETHOXY]ETHOXY]ETHANOIC+ACID'>OP2</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4bn4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bn4 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4bn4 RCSB], [http://www.ebi.ac.uk/pdbsum/4bn4 PDBsum]</span></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=4bn4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bn4 OCA], [https://pdbe.org/4bn4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bn4 RCSB], [https://www.ebi.ac.uk/pdbsum/4bn4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bn4 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/SIR3_HUMAN SIR3_HUMAN]] NAD-dependent protein deacetylase. Activates mitochondrial target proteins, including ACSS1, IDH2 and GDH by deacetylating key lysine residues. Contributes to the regulation of the cellular energy metabolism. Important for regulating tissue-specific ATP levels.<ref>PMID:16788062</ref> <ref>PMID:18680753</ref> <ref>PMID:18794531</ref> <ref>PMID:19535340</ref>
+[https://www.uniprot.org/uniprot/SIR3_HUMAN SIR3_HUMAN] NAD-dependent protein deacetylase. Activates mitochondrial target proteins, including ACSS1, IDH2 and GDH by deacetylating key lysine residues. Contributes to the regulation of the cellular energy metabolism. Important for regulating tissue-specific ATP levels.<ref>PMID:16788062</ref> <ref>PMID:18680753</ref> <ref>PMID:18794531</ref> <ref>PMID:19535340</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 17: / Line 18: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4bn4" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Histone deacetylase 3D structures|Histone deacetylase 3D structures]]
 == References ==
 <references/>
@@ Line 22: / Line 27: @@
 </StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Gertz, M]]
+[[Category: Large Structures]]
-[[Category: Nguyen, G T.T]]
+[[Category: Gertz M]]
-[[Category: Schaefer, S]]
+[[Category: Nguyen GTT]]
-[[Category: Steegborn, C]]
+[[Category: Schaefer S]]
-[[Category: Weyand, M]]
+[[Category: Steegborn C]]
-[[Category: Adp ribose]]
+[[Category: Weyand M]]
-[[Category: Hydrolase]]
-[[Category: Lysine deacetylase]]

4bn4

From Proteopedia

Current revision

Structure of human SIRT3 in complex with ADP-ribose

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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