5y5n

From Proteopedia

(Difference between revisions)

Revision as of 09:14, 18 December 2019

Crystal structure of human Sirtuin 2 in complex with a selective inhibitor

Structural highlights

5y5n is a 1 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:	SIRT2, SIR2L, SIR2L2 (HUMAN)
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

Sirtuin 2 (SIRT2), a member of the NAD(+)-dependent histone deacetylase family, has recently received increasing attention due to its potential involvement in neurodegenerative diseases and the progression of cancer. Potent and selective SIRT2 inhibitors thus represent desirable biological probes. Based on the X-ray crystal structure of SIRT2 in complex with a previously reported weak inhibitor (6), we identified in this study the potent mechanism-based inactivator KPM-2 (36), which is selective toward SIRT2. Compound 36 engages in a nucleophilic attack toward NAD(+) at the active site of SIRT2, which affords a stable 36-ADP-ribose conjugate that simultaneously occupies the substrate-binding site, the "selectivity pocket" and the NAD(+)-binding site. Moreover, 36 exhibits antiproliferative activity in cancer cells and remarkable neurite outgrowth activity. This strategy for the selective inhibition of SIRT2 should allow further probing of the biology of SIRT2, and promote the development of new disease treatment strategies.

Potent mechanism-based sirtuin-2-selective inhibition by an in situ-generated occupant of the substrate-binding site, "selectivity pocket" and NAD(+)-binding site.,Mellini P, Itoh Y, Tsumoto H, Li Y, Suzuki M, Tokuda N, Kakizawa T, Miura Y, Takeuchi J, Lahtela-Kakkonen M, Suzuki T Chem Sci. 2017 Sep 1;8(9):6400-6408. doi: 10.1039/c7sc02738a. Epub 2017 Jul 21. PMID:28989670^[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
↑ Mellini P, Itoh Y, Tsumoto H, Li Y, Suzuki M, Tokuda N, Kakizawa T, Miura Y, Takeuchi J, Lahtela-Kakkonen M, Suzuki T. Potent mechanism-based sirtuin-2-selective inhibition by an in situ-generated occupant of the substrate-binding site, "selectivity pocket" and NAD(+)-binding site. Chem Sci. 2017 Sep 1;8(9):6400-6408. doi: 10.1039/c7sc02738a. Epub 2017 Jul 21. PMID:28989670 doi:http://dx.doi.org/10.1039/c7sc02738a

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/5y5n"

@@ Line 1: / Line 1: @@
 ==Crystal structure of human Sirtuin 2 in complex with a selective inhibitor==
-<StructureSection load='5y5n' size='340' side='right' caption='[[5y5n]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
+<StructureSection load='5y5n' size='340' side='right'caption='[[5y5n]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5y5n]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5Y5N OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5Y5N FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5y5n]] 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=5Y5N OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5Y5N FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8NO:2-[[3-(2-phenylethoxy)phenyl]amino]benzamide'>8NO</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">SIRT2, SIR2L, SIR2L2 ([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=5y5n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5y5n OCA], [http://pdbe.org/5y5n PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5y5n RCSB], [http://www.ebi.ac.uk/pdbsum/5y5n PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5y5n 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 ==
+Sirtuin 2 (SIRT2), a member of the NAD(+)-dependent histone deacetylase family, has recently received increasing attention due to its potential involvement in neurodegenerative diseases and the progression of cancer. Potent and selective SIRT2 inhibitors thus represent desirable biological probes. Based on the X-ray crystal structure of SIRT2 in complex with a previously reported weak inhibitor (6), we identified in this study the potent mechanism-based inactivator KPM-2 (36), which is selective toward SIRT2. Compound 36 engages in a nucleophilic attack toward NAD(+) at the active site of SIRT2, which affords a stable 36-ADP-ribose conjugate that simultaneously occupies the substrate-binding site, the "selectivity pocket" and the NAD(+)-binding site. Moreover, 36 exhibits antiproliferative activity in cancer cells and remarkable neurite outgrowth activity. This strategy for the selective inhibition of SIRT2 should allow further probing of the biology of SIRT2, and promote the development of new disease treatment strategies.
+Potent mechanism-based sirtuin-2-selective inhibition by an in situ-generated occupant of the substrate-binding site, "selectivity pocket" and NAD(+)-binding site.,Mellini P, Itoh Y, Tsumoto H, Li Y, Suzuki M, Tokuda N, Kakizawa T, Miura Y, Takeuchi J, Lahtela-Kakkonen M, Suzuki T Chem Sci. 2017 Sep 1;8(9):6400-6408. doi: 10.1039/c7sc02738a. Epub 2017 Jul 21. PMID:28989670<ref>PMID:28989670</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 5y5n" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Histone deacetylase 3D structures|Histone deacetylase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Itoh, Y]]
 [[Category: Kakizawa, T]]

5y5n

From Proteopedia

Revision as of 09:14, 18 December 2019

Crystal structure of human Sirtuin 2 in complex with a selective inhibitor

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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