5DY5

Crystal structure of human Sirt2 in complex with a SirReal probe fragment

Summary for 5DY5

• Entry DOI: 10.2210/pdb5dy5/pdb
• Descriptor: NAD-dependent protein deacetylase sirtuin-2, ZINC ION, N-(5-{3-[(1-benzyl-1H-1,2,3-triazol-4-yl)methoxy]benzyl}-1,3-thiazol-2-yl)-2-[(4,6-dimethylpyrimidin-2-yl)sulfanyl]acetamide, ... (7 entities in total)
• Functional Keywords: hydrolase, hydrolase inhibitor complex
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus. Isoform 1: Cytoplasm . Isoform 2: Cytoplasm . Isoform 5: Cytoplasm : Q8IXJ6
• Total number of polymer chains: 1
• Total formula weight: 35430.32

Authors

Rumpf, T.,Gerhardt, S.,Einsle, O.,Jung, M. (deposition date: 2015-09-24, release date: 2016-01-20, Last modification date: 2024-01-10)

Primary citation

Schiedel, M.,Rumpf, T.,Karaman, B.,Lehotzky, A.,Gerhardt, S.,Ovadi, J.,Sippl, W.,Einsle, O.,Jung, M.
Structure-Based Development of an Affinity Probe for Sirtuin 2.
Angew.Chem.Int.Ed.Engl., 55:2252-2256, 2016

PubMed Abstract: Sirtuins are NAD(+)-dependent protein deacylases that cleave off acetyl groups, as well as other acyl groups, from the ɛ-amino group of lysines in histones and other substrate proteins. Dysregulation of human Sirt2 activity has been associated with the pathogenesis of cancer, inflammation, and neurodegeneration, thus making Sirt2 a promising target for pharmaceutical intervention. Here, based on a crystal structure of Sirt2 in complex with an optimized sirtuin rearranging ligand (SirReal) that shows improved potency, water solubility, and cellular efficacy, we present the development of the first Sirt2-selective affinity probe. A slow dissociation of the probe/enzyme complex offers new applications for SirReals, such as biophysical characterization, fragment-based screening, and affinity pull-down assays. This possibility makes the SirReal probe an important tool for studying sirtuin biology.

PubMed: 26748890
DOI: 10.1002/anie.201509843

Experimental method

X-RAY DIFFRACTION (1.95 Å)