9s22

Crystal structure of human SIRT2 in complex with the covalent adduct of SirReal-triazole inhibitor LG023 and ADP-ribose

spinqualitylabelsall models 9s22, resolution 1.95Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9s22 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. Method: X-ray diffraction, Resolution 1.95Å Ligands: A1JK2, ZN 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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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