2NYR

Crystal Structure of Human Sirtuin Homolog 5 in Complex with Suramin

Replaces:  2FZQ

Summary for 2NYR

• Entry DOI: 10.2210/pdb2nyr/pdb
• Descriptor: NAD-dependent deacetylase sirtuin-5, ZINC ION, 8,8'-[CARBONYLBIS[IMINO-3,1-PHENYLENECARBONYLIMINO(4-METHYL-3,1-PHENYLENE)CARBONYLIMINO]]BIS-1,3,5-NAPHTHALENETRISULFON IC ACID, ... (4 entities in total)
• Functional Keywords: histone deacetylase, structural genomics, structural genomics consortium, sgc, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Mitochondrion matrix: Q9NXA8
• Total number of polymer chains: 2
• Total formula weight: 60281.14

Authors

Min, J.R.,Antoshenko, T.,Allali-Hassani, A.,Dong, A.,Weigelt, J.,Sundstrom, M.,Arrowsmith, C.H.,Edwards, A.M.,Bochkarev, A.,Plotnikov, A.N.,Structural Genomics Consortium (SGC) (deposition date: 2006-11-21, release date: 2006-12-19, Last modification date: 2023-08-30)

Primary citation

Schuetz, A.,Min, J.,Antoshenko, T.,Wang, C.L.,Allali-Hassani, A.,Dong, A.,Loppnau, P.,Vedadi, M.,Bochkarev, A.,Sternglanz, R.,Plotnikov, A.N.
Structural basis of inhibition of the human NAD+-dependent deacetylase SIRT5 by suramin.
Structure, 15:377-389, 2007

PubMed Abstract: Sirtuins are NAD(+)-dependent protein deacetylases and are emerging as molecular targets for the development of pharmaceuticals to treat human metabolic and neurological diseases and cancer. To date, several sirtuin inhibitors and activators have been identified, but the structural mechanisms of how these compounds modulate sirtuin activity have not yet been determined. We identified suramin as a compound that binds to human SIRT5 and showed that it inhibits SIRT5 NAD(+)-dependent deacetylase activity with an IC(50) value of 22 microM. To provide insights into how sirtuin function is altered by inhibitors, we determined two crystal structures of SIRT5, one in complex with ADP-ribose, the other bound to suramin. Our structural studies provide a view of a synthetic inhibitory compound in a sirtuin active site revealing that suramin binds into the NAD(+), the product, and the substrate-binding site. Finally, our structures may enable the rational design of more potent inhibitors.

PubMed: 17355872
DOI: 10.1016/j.str.2007.02.002

Experimental method

X-RAY DIFFRACTION (2.06 Å)