5GXO

Discovery of a compound that activates SIRT3 to deacetylate Manganese Superoxide Dismutase

Summary for 5GXO

• Entry DOI: 10.2210/pdb5gxo/pdb
• Descriptor: Superoxide dismutase [Mn], mitochondrial, MANGANESE (II) ION (3 entities in total)
• Functional Keywords: superoxide dismutase acetylation, oxidoreductase
• Biological source: Homo sapiens (Human)
• Cellular location: Mitochondrion matrix: P04179
• Total number of polymer chains: 2
• Total formula weight: 44658.16

Authors

Lu, J.,Li, J.,Wu, M.,Wang, J.,Xia, Q. (deposition date: 2016-09-19, release date: 2017-08-09, Last modification date: 2024-10-16)

Primary citation

Lu, J.,Zhang, H.,Chen, X.,Zou, Y.,Li, J.,Wang, L.,Wu, M.,Zang, J.,Yu, Y.,Zhuang, W.,Xia, Q.,Wang, J.
A small molecule activator of SIRT3 promotes deacetylation and activation of manganese superoxide dismutase.
Free Radic. Biol. Med., 112:287-297, 2017

PubMed Abstract: The modulation of protein acetylation network is a promising strategy for life span extension and disease treatment (Sabari et al., 2016; Giblin et al., 2014) [1,2]. A variety of small molecules have been developed to target deacetylases, but extremely few of these molecules are capable of activating the mitochondrial NAD-dependent deacetylase sirtuin-3 (SIRT3) (Gertz and Steegborn, 2016; Scholz et al., 2015) [3,4]. Manganese superoxide dismutase (MnSOD) is the major superoxide scavenger in mitochondria, whose activity is regulated by SIRT3-mediated deacetylation, particularly at the Lys68 site (Chen et al., 2011) [5]. To investigate the influence of Lys68 acetylation on MnSOD activity, we produced a mutant MnSOD protein-bearing N-acetyllysine (AcK) at its Lys68 position through the genetic code expansion approach. We solved the crystal structure of this acetylated MnSOD (MnSODK68AcK), thus revealing the structural and electrostatic basis for the significant activity decrease upon Lys68 acetylation. On the basis of an assay we developed for the SIRT3-mediated deacetylation of MnSODK68AcK, we identified a novel SIRT3 activator, 7-hydroxy-3-(4'-methoxyphenyl) coumarin (C12), which binds to SIRT3 with high affinity and can promote the deacetylation and activation of MnSOD. C12 adds to the current repertoire of extremely few SIRT3 activators, which are potentially valuable for treating a wide array of diseases via modulating the cellular acetylome.

PubMed: 28711502
DOI: 10.1016/j.freeradbiomed.2017.07.012

Experimental method

X-RAY DIFFRACTION (2.3 Å)