View source for 9s22


==Crystal structure of human SIRT2 in complex with the covalent adduct of SirReal-triazole inhibitor LG023 and ADP-ribose==
<StructureSection load='9s22' size='340' side='right'caption='[[9s22]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9s22]] 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=9S22 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9S22 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.95&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1JK2:[[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl]+[(2~{R},3~{S},4~{R},5~{S})-5-[5-[[3-[[2-[2-(4,6-dimethylpyrimidin-2-yl)sulfanylethanoylamino]-1,3-thiazol-5-yl]methyl]phenoxy]methyl]-1,2,3-triazol-1-yl]-3,4-bis(oxidanyl)oxolan-2-yl]methyl+hydrogen+phosphate'>A1JK2</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'>[https://proteopedia.org/fgij/fg.htm?mol=9s22 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9s22 OCA], [https://pdbe.org/9s22 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9s22 RCSB], [https://www.ebi.ac.uk/pdbsum/9s22 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9s22 ProSAT]</span></td></tr>
</table>
== Function ==
[https://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 (SIRTs) are nicotinamide adenine dinucleotide (NAD(+))-dependent lysine deacylases linked to key physiological and disease processes. Here, we report a new class of mechanism-based 1,2,3-triazole inhibitors that hijack SIRT catalysis by forming stalled triazolium- or triazole-ADP-ribose (ADPR) adducts derived from the cofactor NAD(+). These trapped adducts inhibit the enzyme without covalent protein modification, prompting us to term the compounds "Sirtuin Trapping Ligands" (SirTraps). X-ray crystallography and kinetics, together with mass spectrometry confirming adduct formation both in vitro and in cellulo, reveal that the triazole N3 of peptide- and small-molecule-based SirTraps triggers nucleophilic attack at C1' of the nicotinamide riboside moiety of NAD(+), mimicking the first deacylation step. Adduct formation critically depends on precise triazole positioning within the acyl-lysine channel and can be tuned through scaffold design, enabling potent and isoform-selective inhibition. Unlike thiocarbonyl-based NAD(+)-targeting SIRT inhibitors, which may suffer from instability and off-target effects, SirTraps combine high stability, synthetic accessibility, and structural tunability, while demonstrating nanomolar cellular target engagement confirmed by NanoBRET assays. Beyond SIRTs, this inhibition strategy may extend to other NAD(+)-dependent enzymes, including ADP-ribosyltransferases, opening new avenues for mechanism-driven drug discovery.

From Pharmacophore to Warhead: NAD(+)-Targeting Triazoles as Mechanism-Based Sirtuin Inhibitors.,Friedrich F, Meleshin M, Papenkordt N, Gaitzsch L, Prucker I, Borso M, Ruprecht J, Vorreiter C, Rast S, Zhang L, Schiedel M, Sippl W, Imhof A, Jessen HJ, Einsle O, Schutkowski M, Jung M Angew Chem Int Ed Engl. 2025 Oct 30:e16782. doi: 10.1002/anie.202516782. PMID:41165483<ref>PMID:41165483</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9s22" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Einsle O]]
[[Category: Friedrich F]]
[[Category: Gaitzsch L]]
[[Category: Jung M]]