9FRU
Crystal structure of human Sirt2 in complex with a pyrazole-based fragment inhibitor and NAD+
This is a non-PDB format compatible entry.
Summary for 9FRU
| Entry DOI | 10.2210/pdb9fru/pdb |
| Descriptor | NAD-dependent protein deacetylase sirtuin-2, ZINC ION, 1,2-ETHANEDIOL, ... (7 entities in total) |
| Functional Keywords | inhibitor, sirtuin 2, deacylase, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 35604.05 |
| Authors | Friedrich, F.,Einsle, O.,Jung, M. (deposition date: 2024-06-19, release date: 2025-06-04, Last modification date: 2025-06-25) |
| Primary citation | Friedrich, F.,Schiedel, M.,Swyter, S.,Zhang, L.,Sippl, W.,Schutkowski, M.,Einsle, O.,Jung, M. Efficient Crystallization of Apo Sirt2 for Small-Molecule Soaking and Structural Analysis of Ligand Interactions. J.Med.Chem., 68:10771-10780, 2025 Cited by PubMed Abstract: The selectivity pocket is a key binding site for inhibitors of the NAD-dependent lysine deacylase Sirtuin 2 (Sirt2), a promising drug target in diseases like cancer. While small-molecule soaking can advance inhibitor development, the selectivity pocket is absent in available Sirt2 apo structures, and existing soaking systems like Sirt2-ADPribose (ADPR) suffer from unfavorable crystal packing that hinders ligand binding. We developed a method to rapidly generate high-quality Sirt2 apo crystals with an open selectivity pocket, suitable for high-throughput soaking. The induced-fit pocket forms upon seeding with a Sirtuin Rearranging ligand (SirReal) and is retained in the ligand-free apo structure. Screening the Maybridge Ro3-fragment library using a fluorescence polarization assay yielded three novel Sirt2-fragment-inhibitor structures. Additionally, our Sirt2 apo crystals can accommodate ligands at the acyl-lysine channel entrance and the cofactor binding site, as confirmed by binding of the peptide inhibitor KT9 and NAD, facilitating SAR studies and inhibitor optimization. PubMed: 40390200DOI: 10.1021/acs.jmedchem.4c02896 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
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