9S22

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

This is a non-PDB format compatible entry.

Summary for 9S22

• Entry DOI: 10.2210/pdb9s22/pdb
• Descriptor: NAD-dependent protein deacetylase sirtuin-2, ZINC ION, [[(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, ... (4 entities in total)
• Functional Keywords: sirtuins, inhibitor, covalent adduct, deacetylation, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 35491.00

Authors

Friedrich, F.,Gaitzsch, L.,Einsle, O.,Jung, M. (deposition date: 2025-07-21, release date: 2025-11-12, Last modification date: 2026-01-14)

Primary citation

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, H.J.,Einsle, O.,Schutkowski, M.,Jung, M.
From Pharmacophore to Warhead: NAD + -Targeting Triazoles as Mechanism-Based Sirtuin Inhibitors.
Angew.Chem.Int.Ed.Engl., 64:e16782-e16782, 2025

PubMed Abstract: 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.

PubMed: 41165483
DOI: 10.1002/anie.202516782

Experimental method

X-RAY DIFFRACTION (1.95 Å)