9KTK

Crystal structure of human SIRT3 with its activator SKLB-11A

This is a non-PDB format compatible entry.

Summary for 9KTK

• Entry DOI: 10.2210/pdb9ktk/pdb
• Descriptor: NAD-dependent protein deacetylase sirtuin-3, mitochondrial, ZINC ION, methyl 2-azanyl-1-[(4-fluorophenyl)methyl]pyrrolo[3,2-b]quinoxaline-3-carboxylate, ... (4 entities in total)
• Functional Keywords: sirt3 activator cardioprotection, structural protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 124933.70

Authors

Ouyang, L.,Wu, C.Y. (deposition date: 2024-12-02, release date: 2025-06-25)

Primary citation

Zhang, D.,Zhang, J.,Wu, C.,Xiao, Y.,Ji, L.,Hu, J.,Ding, J.,Li, T.,Zhang, Y.,Ouyang, L.
Unraveling Small Molecule-Mediated Sirtuin 3 Activation at a Distinct Binding Site for Cardioprotective Therapies.
Acs Cent.Sci., 11:704-718, 2025

PubMed Abstract: Sirtuin 3 (SIRT3), a pivotal mitochondrial deacetylase, plays a critical role in restoring mitochondrial function, particularly through the activation of autophagy. Despite its promise as a cardioprotective target, developing SIRT3 activators and their therapeutic applications remains challenging. Here, we report the identification of , a SIRT3 activator with submicromolar affinity and high efficacy. Structural and mutagenesis analyses revealed a unique allosteric site for in SIRT3, where a conformational change in Leu298 drives its potent activation. Subsequent studies demonstrated that drives autophagy/mitophagy signaling pathways, effectively preventing mitochondrial dysfunction, and improving cardiac dysfunction in both doxorubicin (Dox)-induced cardiotoxicity and myocardial ischemia/reperfusion (I/R) models. Collectively, our data highlight the potential of pharmacological SIRT3 activation as an effective therapeutic strategy for cardioprotection. , as a first-in-class SIRT3 allosteric activator with a distinct binding mode, not only offers a valuable tool for exploring the physiological and pathological roles of SIRT3 deacetylation but also holds promise for the development of targeted cardioprotective therapies.

PubMed: 40454347
DOI: 10.1021/acscentsci.5c00023

Experimental method

X-RAY DIFFRACTION (2.49 Å)