4UTZ

Crystal structure of zebrafish Sirtuin 5 in complex with adipoylated CPS1-peptide

Summary for 4UTZ

• Entry DOI: 10.2210/pdb4utz/pdb
• Related: 4UTN 4UTR 4UTV 4UTX 4UU7 4UU8 4UUA 4UUB
• Descriptor: SIRTUIN 5, CARBAMOYLPHOSPHATE SYNTHETASE I, ZINC ION, ... (9 entities in total)
• Functional Keywords: hydrolase, sirtuin 5, regulatory enzyme, deacylase, mitochondrial, rossmann-fold, zinc-binding
• Biological source: DANIO RERIO (ZEBRAFISH); More
• Cellular location: Mitochondrion (By similarity): Q6DHI5
• Total number of polymer chains: 3
• Total formula weight: 62495.14

Authors

Pannek, M.,Gertz, M.,Steegborn, C. (deposition date: 2014-07-24, release date: 2014-08-20, Last modification date: 2024-01-31)

Primary citation

Roessler, C.,Nowak, T.,Pannek, M.,Gertz, M.,Nguyen, G.T.,Scharfe, M.,Born, I.,Sippl, W.,Steegborn, C.,Schutkowski, M.
Chemical Probing of the Human Sirtuin 5 Active Site Reveals its Substrate Acyl Specificity and Peptide-Based Inhibitors.
Angew.Chem.Int.Ed.Engl., 53:10728-, 2014

PubMed Abstract: Sirtuins are NAD(+)-dependent deacetylases acting as sensors in metabolic pathways and stress response. In mammals there are seven isoforms. The mitochondrial sirtuin 5 is a weak deacetylase but a very efficient demalonylase and desuccinylase; however, its substrate acyl specificity has not been systematically analyzed. Herein, we investigated a carbamoyl phosphate synthetase 1 derived peptide substrate and modified the lysine side chain systematically to determine the acyl specificity of Sirt5. From that point we designed six potent peptide-based inhibitors that interact with the NAD(+) binding pocket. To characterize the interaction details causing the different substrate and inhibition properties we report several X-ray crystal structures of Sirt5 complexed with these peptides. Our results reveal the Sirt5 acyl selectivity and its molecular basis and enable the design of inhibitors for Sirt5.

PubMed: 25111069
DOI: 10.1002/ANIE.201402679

Experimental method

X-RAY DIFFRACTION (3.3 Å)