5gxo

From Proteopedia

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

PDB ID 5gxo

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Structural highlights

5gxo is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.3Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

SODM_HUMAN Genetic variation in SOD2 is associated with susceptibility to microvascular complications of diabetes type 6 (MVCD6) [MIM:612634. These are pathological conditions that develop in numerous tissues and organs as a consequence of diabetes mellitus. They include diabetic retinopathy, diabetic nephropathy leading to end-stage renal disease, and diabetic neuropathy. Diabetic retinopathy remains the major cause of new-onset blindness among diabetic adults. It is characterized by vascular permeability and increased tissue ischemia and angiogenesis.

Function

SODM_HUMAN Destroys superoxide anion radicals which are normally produced within the cells and which are toxic to biological systems.^[1]

Publication Abstract from PubMed

The modulation of protein acetylation network is a promising strategy for life span extension and disease treatment.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).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.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 (MnSODLys68AcK), 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 MnSODLys68AcK, we identified a novel SIRT3 activator, 7-hydroxy-3-(4'-methoxyphenyl) coumarin, 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.

A Small Molecule Activator of SIRT3 Promotes Deacetylation and Activation of Manganese Superoxide Dismutase.,Lu J, Zhang H, Chen X, Zou Y, Li J, Wang L, Wu M, Zang J, Yu Y, Zhuang W, Xia Q, Wang J Free Radic Biol Med. 2017 Jul 12. pii: S0891-5849(17)30684-6. doi:, 10.1016/j.freeradbiomed.2017.07.012. PMID:28711502^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ MacMillan-Crow LA, Thompson JA. Tyrosine modifications and inactivation of active site manganese superoxide dismutase mutant (Y34F) by peroxynitrite. Arch Biochem Biophys. 1999 Jun 1;366(1):82-8. PMID:10334867 doi:S0003-9861(99)91202-X
↑ 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. 2017 Jul 12. pii: S0891-5849(17)30684-6. doi:, 10.1016/j.freeradbiomed.2017.07.012. PMID:28711502 doi:http://dx.doi.org/10.1016/j.freeradbiomed.2017.07.012