5mar

From Proteopedia

(Difference between revisions)

Revision as of 21:08, 15 March 2017

Structure of human SIRT2 in complex with 1,2,4-Oxadiazole inhibitor and ADP ribose.

Structural highlights

5mar is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , , , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[SIR2_HUMAN] NAD-dependent protein deacetylase, which deacetylates internal lysines on histone and non-histone proteins. Deacetylates 'Lys-40' of alpha-tubulin. Involved in the control of mitotic exit in the cell cycle, probably via its role in the regulation of cytoskeleton. Deacetylates PCK1, opposing proteasomal degradation. Deacetylates 'Lys-310' of RELA.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Sirt2 is a target for the treatment of neurological, metabolic, and age-related diseases including cancer. Here we report a series of Sirt2 inhibitors based on the 1,2,4-oxadiazole scaffold. These compounds are potent Sirt2 inhibitors active at single-digit muM level by using the Sirt2 substrate alpha-tubulin-acetylLys40 peptide and inactive up to 100 muM against Sirt1, -3, and -5 (deacetylase and desuccinylase activities). Their mechanism of inhibition is uncompetitive toward both the peptide substrate and NAD+, and the crystal structure of a 1,2,4-oxadiazole analog in complex with Sirt2 and ADP-ribose reveals its orientation in a still unexplored subcavity useful for further inhibitor development. Tested in leukemia cell lines, 35 and 39 induced apoptosis and/or showed antiproliferative effects at 10 or 25 muM after 48 h. Western blot analyses confirmed the involvement of Sirt2 inhibition for their effects in NB4 and in U937 cells. Our results provide novel Sirt2 inhibitors with a compact scaffold and structural insights for further inhibitor improvement.

Development of 1,2,4-Oxadiazoles as Potent and Selective Inhibitors of the Human Deacetylase Sirtuin 2: Structure-Activity Relationship, X-ray Crystal Structure, and Anticancer Activity.,Moniot S, Forgione M, Lucidi A, Hailu GS, Nebbioso A, Carafa V, Baratta F, Altucci L, Giacche N, Passeri D, Pellicciari R, Mai A, Steegborn C, Rotili D J Med Chem. 2017 Mar 14. doi: 10.1021/acs.jmedchem.6b01609. PMID:28240897^[5]

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

References

↑ North BJ, Marshall BL, Borra MT, Denu JM, Verdin E. The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol Cell. 2003 Feb;11(2):437-44. PMID:12620231
↑ Dryden SC, Nahhas FA, Nowak JE, Goustin AS, Tainsky MA. Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle. Mol Cell Biol. 2003 May;23(9):3173-85. PMID:12697818
↑ Rothgiesser KM, Erener S, Waibel S, Luscher B, Hottiger MO. SIRT2 regulates NF-kappaB dependent gene expression through deacetylation of p65 Lys310. J Cell Sci. 2010 Dec 15;123(Pt 24):4251-8. doi: 10.1242/jcs.073783. Epub 2010 Nov, 16. PMID:21081649 doi:10.1242/jcs.073783
↑ Jiang W, Wang S, Xiao M, Lin Y, Zhou L, Lei Q, Xiong Y, Guan KL, Zhao S. Acetylation regulates gluconeogenesis by promoting PEPCK1 degradation via recruiting the UBR5 ubiquitin ligase. Mol Cell. 2011 Jul 8;43(1):33-44. doi: 10.1016/j.molcel.2011.04.028. PMID:21726808 doi:10.1016/j.molcel.2011.04.028
↑ Moniot S, Forgione M, Lucidi A, Hailu GS, Nebbioso A, Carafa V, Baratta F, Altucci L, Giacche N, Passeri D, Pellicciari R, Mai A, Steegborn C, Rotili D. Development of 1,2,4-Oxadiazoles as Potent and Selective Inhibitors of the Human Deacetylase Sirtuin 2: Structure-Activity Relationship, X-ray Crystal Structure, and Anticancer Activity. J Med Chem. 2017 Mar 14. doi: 10.1021/acs.jmedchem.6b01609. PMID:28240897 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b01609

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/5mar"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 5mar is ON HOLD
+==Structure of human SIRT2 in complex with 1,2,4-Oxadiazole inhibitor and ADP ribose.==
+<StructureSection load='5mar' size='340' side='right' caption='[[5mar]], [[Resolution|resolution]] 1.89&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5mar]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MAR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5MAR FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7KE:3-[3-(4-CHLOROPHENYL)-1,2,4-OXADIAZOL-5-YL]PROPAN-1-OL'>7KE</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</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=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=5mar FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mar OCA], [http://pdbe.org/5mar PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mar RCSB], [http://www.ebi.ac.uk/pdbsum/5mar PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mar ProSAT]</span></td></tr>
+</table>
+== Function ==
+[[http://www.uniprot.org/uniprot/SIR2_HUMAN SIR2_HUMAN]] NAD-dependent protein deacetylase, which deacetylates internal lysines on histone and non-histone proteins. Deacetylates 'Lys-40' of alpha-tubulin. Involved in the control of mitotic exit in the cell cycle, probably via its role in the regulation of cytoskeleton. Deacetylates PCK1, opposing proteasomal degradation. Deacetylates 'Lys-310' of RELA.<ref>PMID:12620231</ref> <ref>PMID:12697818</ref> <ref>PMID:21081649</ref> <ref>PMID:21726808</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Sirt2 is a target for the treatment of neurological, metabolic, and age-related diseases including cancer. Here we report a series of Sirt2 inhibitors based on the 1,2,4-oxadiazole scaffold. These compounds are potent Sirt2 inhibitors active at single-digit muM level by using the Sirt2 substrate alpha-tubulin-acetylLys40 peptide and inactive up to 100 muM against Sirt1, -3, and -5 (deacetylase and desuccinylase activities). Their mechanism of inhibition is uncompetitive toward both the peptide substrate and NAD+, and the crystal structure of a 1,2,4-oxadiazole analog in complex with Sirt2 and ADP-ribose reveals its orientation in a still unexplored subcavity useful for further inhibitor development. Tested in leukemia cell lines, 35 and 39 induced apoptosis and/or showed antiproliferative effects at 10 or 25 muM after 48 h. Western blot analyses confirmed the involvement of Sirt2 inhibition for their effects in NB4 and in U937 cells. Our results provide novel Sirt2 inhibitors with a compact scaffold and structural insights for further inhibitor improvement.
-Authors:
+Development of 1,2,4-Oxadiazoles as Potent and Selective Inhibitors of the Human Deacetylase Sirtuin 2: Structure-Activity Relationship, X-ray Crystal Structure, and Anticancer Activity.,Moniot S, Forgione M, Lucidi A, Hailu GS, Nebbioso A, Carafa V, Baratta F, Altucci L, Giacche N, Passeri D, Pellicciari R, Mai A, Steegborn C, Rotili D J Med Chem. 2017 Mar 14. doi: 10.1021/acs.jmedchem.6b01609. PMID:28240897<ref>PMID:28240897</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 5mar" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Moniot, S]]
+[[Category: Steegborn, C]]
+[[Category: Hydrolase]]
+[[Category: Inhibitor complex]]
+[[Category: Nad-dependent protein deacylase]]
+[[Category: Sirtuin]]

5mar

From Proteopedia

Revision as of 21:08, 15 March 2017

Structure of human SIRT2 in complex with 1,2,4-Oxadiazole inhibitor and ADP ribose.

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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