4rmh
From Proteopedia
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| - | ''' | + | ==Human Sirt2 in complex with SirReal2 and Ac-Lys-H3 peptide== |
| + | <StructureSection load='4rmh' size='340' side='right' caption='[[4rmh]], [[Resolution|resolution]] 1.42Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[4rmh]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RMH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RMH FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3TE:2-[(4,6-DIMETHYLPYRIMIDIN-2-YL)SULFANYL]-N-[5-(NAPHTHALEN-1-YLMETHYL)-1,3-THIAZOL-2-YL]ACETAMIDE'>3TE</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | ||
| + | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ALY:N(6)-ACETYLLYSINE'>ALY</scene></td></tr> | ||
| + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4rmg|4rmg]], [[4rmi|4rmi]], [[4rmj|4rmj]]</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=4rmh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rmh OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4rmh RCSB], [http://www.ebi.ac.uk/pdbsum/4rmh PDBsum]</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 == | ||
| + | Sirtuins are a highly conserved class of NAD(+)-dependent lysine deacylases. The human isotype Sirt2 has been implicated in the pathogenesis of cancer, inflammation and neurodegeneration, which makes the modulation of Sirt2 activity a promising strategy for pharmaceutical intervention. A rational basis for the development of optimized Sirt2 inhibitors is lacking so far. Here we present high-resolution structures of human Sirt2 in complex with highly selective drug-like inhibitors that show a unique inhibitory mechanism. Potency and the unprecedented Sirt2 selectivity are based on a ligand-induced structural rearrangement of the active site unveiling a yet-unexploited binding pocket. Application of the most potent Sirtuin-rearranging ligand, termed SirReal2, leads to tubulin hyperacetylation in HeLa cells and induces destabilization of the checkpoint protein BubR1, consistent with Sirt2 inhibition in vivo. Our structural insights into this unique mechanism of selective sirtuin inhibition provide the basis for further inhibitor development and selective tools for sirtuin biology. | ||
| - | + | Selective Sirt2 inhibition by ligand-induced rearrangement of the active site.,Rumpf T, Schiedel M, Karaman B, Roessler C, North BJ, Lehotzky A, Olah J, Ladwein KI, Schmidtkunz K, Gajer M, Pannek M, Steegborn C, Sinclair DA, Gerhardt S, Ovadi J, Schutkowski M, Sippl W, Einsle O, Jung M Nat Commun. 2015 Feb 12;6:6263. doi: 10.1038/ncomms7263. PMID:25672491<ref>PMID:25672491</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | == References == | |
| - | + | <references/> | |
| - | + | __TOC__ | |
| - | + | </StructureSection> | |
| - | [[Category: | + | [[Category: Einsle, O]] |
| - | [[Category: | + | [[Category: Gajer, M]] |
| - | + | ||
| - | + | ||
[[Category: Gerhardt, S]] | [[Category: Gerhardt, S]] | ||
[[Category: Jung, M]] | [[Category: Jung, M]] | ||
| + | [[Category: Karaman, B]] | ||
| + | [[Category: Ladwein, K I]] | ||
[[Category: Lehotzky, A]] | [[Category: Lehotzky, A]] | ||
| - | + | [[Category: North, B J]] | |
| - | + | ||
| - | [[Category: North, B | + | |
| - | + | ||
[[Category: Olah, J]] | [[Category: Olah, J]] | ||
| - | [[Category: Gajer, M]] | ||
[[Category: Ovadi, J]] | [[Category: Ovadi, J]] | ||
| + | [[Category: Pannek, M]] | ||
| + | [[Category: Roessler, C]] | ||
| + | [[Category: Rumpf, T]] | ||
[[Category: Schiedel, M]] | [[Category: Schiedel, M]] | ||
| - | [[Category: | + | [[Category: Schmidtkunz, K]] |
| - | [[Category: | + | [[Category: Schutkowski, M]] |
| + | [[Category: Sinclair, D A]] | ||
| + | [[Category: Sippl, W]] | ||
| + | [[Category: Steegborn, C]] | ||
| + | [[Category: Hydrolase-hydrolase inhibitor complex]] | ||
Revision as of 13:48, 25 February 2015
Human Sirt2 in complex with SirReal2 and Ac-Lys-H3 peptide
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