9FDS

Crystal structure of human Sirt2 in complex with SirReal2

Summary for 9FDS

• Entry DOI: 10.2210/pdb9fds/pdb
• Descriptor: NAD-dependent protein deacetylase sirtuin-2, ZINC ION, CHLORIDE ION, ... (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: 35280.61

Authors

Friedrich, F.,Einsle, O.,Jung, M. (deposition date: 2024-05-17, release date: 2025-05-28, 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

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: 40390200
DOI: 10.1021/acs.jmedchem.4c02896

Experimental method

X-RAY DIFFRACTION (1.4 Å)