Target Information
| Target General Information | Top | |||||
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| Target ID |
T91959
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| Target Name |
NAD-dependent deacetylase sirtuin-3 (SIRT3)
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| Synonyms |
hSIRT3; SIR2L3; SIR2-like protein 3; Regulatory protein SIR2 homolog 3
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| Gene Name |
SIRT3
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| Target Type |
Literature-reported target
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[1] | ||||
| Function |
NAD-dependent protein deacetylase (PubMed:12186850, PubMed:12374852, PubMed:16788062, PubMed:18680753, PubMed:18794531, PubMed:23283301, PubMed:24121500, PubMed:24252090, PubMed:19535340). Activates or deactivates mitochondrial target proteins by deacetylating key lysine residues (PubMed:12186850, PubMed:12374852, PubMed:16788062, PubMed:18680753, PubMed:18794531, PubMed:23283301, PubMed:24121500, PubMed:24252090). Known targets include ACSS1, IDH, GDH, SOD2, PDHA1, LCAD, SDHA and the ATP synthase subunit ATP5PO (PubMed:16788062, PubMed:18680753, PubMed:24121500, PubMed:24252090, PubMed:19535340). Contributes to the regulation of the cellular energy metabolism (PubMed:24252090). Important for regulating tissue-specific ATP levels (PubMed:18794531). In response to metabolic stress, deacetylates transcription factor FOXO3 and recruits FOXO3 and mitochondrial RNA polymerase POLRMT to mtDNA to promote mtDNA transcription (PubMed:23283301).
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| BioChemical Class |
Sirtuin family. Class I subfamily
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| UniProt ID | ||||||
| EC Number |
EC 3.5.1.-
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| Sequence |
MAFWGWRAAAALRLWGRVVERVEAGGGVGPFQACGCRLVLGGRDDVSAGLRGSHGARGEP
LDPARPLQRPPRPEVPRAFRRQPRAAAPSFFFSSIKGGRRSISFSVGASSVVGSGGSSDK GKLSLQDVAELIRARACQRVVVMVGAGISTPSGIPDFRSPGSGLYSNLQQYDLPYPEAIF ELPFFFHNPKPFFTLAKELYPGNYKPNVTHYFLRLLHDKGLLLRLYTQNIDGLERVSGIP ASKLVEAHGTFASATCTVCQRPFPGEDIRADVMADRVPRCPVCTGVVKPDIVFFGEPLPQ RFLLHVVDFPMADLLLILGTSLEVEPFASLTEAVRSSVPRLLINRDLVGPLAWHPRSRDV AQLGDVVHGVESLVELLGWTEEMRDLVQRETGKLDGPDK Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T41BXR | |||||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Amiodarone | Ligand Info | |||||
| Structure Description | Crystal structure of human SIRT3 in complex with compound (2-butylbenzofuran-3-yl)(4-(2-(diethylamino)ethoxy)-3,5-diiodophenyl)methanone | PDB:4O8Z | ||||
| Method | X-ray diffraction | Resolution | 2.00 Å | Mutation | No | [2] |
| PDB Sequence |
KLSLQDVAEL
131 IRARACQRVV141 VMVGAGISTP151 SGIPDFSPGS162 GLYSNLQQYD172 LPYPEAIFEL 182 PFFFHNPKPF192 FTLAKELYPG202 NYKPNVTHYF212 LRLLHDKGLL222 LRLYTQNIDG 232 LERVSGIPAS242 KLVEAHGTFA252 SATCTVCQRP262 FPGEDIRADV272 MADRVPRCPV 282 CTGVVKPDIV292 FFGEPLPQRF302 LLHVVDFPMA312 DLLLILGTSL322 EVEPFASLTE 332 AVRSSVPRLL342 INRDLVGPLA352 WHPRSRDVAQ362 LGDVVHGVES372 LVELLGWTEE 382 MRDLVQRETG392 KL
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: Norleucine | Ligand Info | |||||
| Structure Description | Human SIRT3 bound to Ac-ACS peptide and Carba-NAD | PDB:4FVT | ||||
| Method | X-ray diffraction | Resolution | 2.47 Å | Mutation | No | [3] |
| PDB Sequence |
KLSLQDVAEL
131 IRARACQRVV141 VMVGAGISTP151 SGIPDFRSPG161 SGLYSNLQQY171 DLPYPEAIFE 181 LPFFFHNPKP191 FFTLAKELYP201 GNYKPNVTHY211 FLRLLHDKGL221 LLRLYTQNID 231 GLERVSGIPA241 SKLVEAHGTF251 ASATCTVCQR261 PFPGEDIRAD271 VMADRVPRCP 281 VCTGVVKPDI291 VFFGEPLPQR301 FLLHVVDFPM311 ADLLLILGTS321 LEVEPFASLT 331 EAVRSSVPRL341 LINRDLVGPL351 AWHPRSRDVA361 QLGDVVHGVE371 SLVELLGWTE 381 EMRDLVQRET391 GKLD
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Nicotinate and nicotinamide metabolism | hsa00760 | Affiliated Target |
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| Class: Metabolism => Metabolism of cofactors and vitamins | Pathway Hierarchy | ||
| Degree | 10 | Degree centrality | 1.07E-03 | Betweenness centrality | 1.36E-03 |
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| Closeness centrality | 2.22E-01 | Radiality | 1.39E+01 | Clustering coefficient | 8.89E-02 |
| Neighborhood connectivity | 2.85E+01 | Topological coefficient | 1.25E-01 | Eccentricity | 11 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-interacting Proteins | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | Central carbon metabolism in cancer | |||||
| References | Top | |||||
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| REF 1 | The NAD+-dependent deacetylase SIRT2 attenuates oxidative stress and mitochondrial dysfunction and improves insulin sensitivity in hepatocytes. Hum Mol Genet. 2017 Nov 1;26(21):4105-4117. | |||||
| REF 2 | Crystal structure of human SIRT3 in complex with compound (2-butylbenzofuran-3-yl)(4-(2-(diethylamino)ethoxy)-3,5-diiodophenyl)methanone | |||||
| REF 3 | Synthesis of carba-NAD and the structures of its ternary complexes with SIRT3 and SIRT5. J Org Chem. 2012 Sep 7;77(17):7319-29. | |||||
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