4jt9: Difference between revisions

Revision as of 11:24, 30 November 2022

Crystal Structure of human SIRT3 with ELT inhibitor 3 [14-(4-{2-[(methylsulfonyl)amino]ethyl}piperidin-1-yl)thieno[3,2-d]pyrimidine-6-carboxamide]

Structural highlights

4jt9 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.
Ligands:	1NS, GOL, NA, ZN
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

The sirtuins SIRT1, SIRT2 and SIRT3 are NAD+ dependent deacetylases that are considered potential targets for metabolic, inflammatory, oncologic and neurodegenerative disorders. Encoded Library Technology (ELT) was used to affinity screen a 1.2 million heterocycle enriched library of DNA encoded small molecules, which identified pan-inhibitors of SIRT1/2/3 with nanomolar potency (e.g. 11c: IC50 = 3.6, 2.7 and 4.0 nM for SIRT1, SIRT2 and SIRT3 respectively). Subsequent SAR studies to improve physiochemical properties identified the potent drug like analogs 28 and 31. Crystallographic studies of 11c, 28 and 31 bound in the SIRT3 active site revealed that the common carboxamide binds in the nicotinamide C-pocket and the aliphatic portions of the inhibitors extend through the substrate channel, explaining the observable SAR. These pan SIRT1/2/3 inhibitors, representing a novel chemotype, are significantly more potent than currently available inhibitors which makes them valuable tools for sirtuin research.

Discovery of Thieno[3,2-d]pyrimidine-6-carboxamides as potent inhibitors of SIRT1, SIRT2 and SIRT3.,Disch JS, Evindar G, Chui CH, Blum CA, Dai H, Jin L, Schuman E, Lind KE, Belyanskaya SL, Deng J, Coppo FT, Aquilani L, Graybill TL, Cuozzo JW, Lavu S, Mao C, Vlasuk GP, Perni RB J Med Chem. 2013 Apr 9. PMID:23570514^[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
↑ Disch JS, Evindar G, Chui CH, Blum CA, Dai H, Jin L, Schuman E, Lind KE, Belyanskaya SL, Deng J, Coppo FT, Aquilani L, Graybill TL, Cuozzo JW, Lavu S, Mao C, Vlasuk GP, Perni RB. Discovery of Thieno[3,2-d]pyrimidine-6-carboxamides as potent inhibitors of SIRT1, SIRT2 and SIRT3. J Med Chem. 2013 Apr 9. PMID:23570514 doi:10.1021/jm400204k

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OCA

[1] 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

[2] 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

[3] 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

[4] 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

[5] Disch JS, Evindar G, Chui CH, Blum CA, Dai H, Jin L, Schuman E, Lind KE, Belyanskaya SL, Deng J, Coppo FT, Aquilani L, Graybill TL, Cuozzo JW, Lavu S, Mao C, Vlasuk GP, Perni RB. Discovery of Thieno[3,2-d]pyrimidine-6-carboxamides as potent inhibitors of SIRT1, SIRT2 and SIRT3. J Med Chem. 2013 Apr 9. PMID:23570514 doi:10.1021/jm400204k

[1]

[2]

[3]

[4]

[5]

@@ Line 1: / Line 1: @@
 ==Crystal Structure of human SIRT3 with ELT inhibitor 3 [14-(4-{2-[(methylsulfonyl)amino]ethyl}piperidin-1-yl)thieno[3,2-d]pyrimidine-6-carboxamide]==
-<StructureSection load='4jt9' size='340' side='right' caption='[[4jt9]], [[Resolution|resolution]] 2.24&Aring;' scene=''>
+<StructureSection load='4jt9' size='340' side='right'caption='[[4jt9]], [[Resolution|resolution]] 2.24&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4jt9]] is a 1 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=4JT9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4JT9 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4jt9]] 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=4JT9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4JT9 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1NS:4-(4-{2-[(METHYLSULFONYL)AMINO]ETHYL}PIPERIDIN-1-YL)THIENO[3,2-D]PYRIMIDINE-6-CARBOXAMIDE'>1NS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1NS:4-(4-{2-[(METHYLSULFONYL)AMINO]ETHYL}PIPERIDIN-1-YL)THIENO[3,2-D]PYRIMIDINE-6-CARBOXAMIDE'>1NS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4jsr|4jsr]], [[4jt8|4jt8]]</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=4jt9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jt9 OCA], [https://pdbe.org/4jt9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4jt9 RCSB], [https://www.ebi.ac.uk/pdbsum/4jt9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4jt9 ProSAT]</span></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SIRT3, SIR2L3 ([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=4jt9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jt9 OCA], [http://pdbe.org/4jt9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4jt9 RCSB], [http://www.ebi.ac.uk/pdbsum/4jt9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4jt9 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 22: / Line 20: @@
 ==See Also==
-*[[Histone deacetylase|Histone deacetylase]]
+*[[Histone deacetylase 3D structures|Histone deacetylase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
-[[Category: Dai, H]]
+[[Category: Large Structures]]
-[[Category: Deacetylase]]
+[[Category: Dai H]]
-[[Category: Hydrolase-hydrolase inhibitor complex]]

4jt9: Difference between revisions

Revision as of 11:24, 30 November 2022

Crystal Structure of human SIRT3 with ELT inhibitor 3 [14-(4-{2-[(methylsulfonyl)amino]ethyl}piperidin-1-yl)thieno[3,2-d]pyrimidine-6-carboxamide]

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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