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PDBsum entry 4jt9

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protein ligands metals links
Hydrolase/hydrolase inhibitor PDB id
4jt9
Jmol
Contents
Protein chain
274 a.a.
Ligands
1NS
GOL ×2
Metals
_NA
_ZN
Waters ×191
PDB id:
4jt9
Name: Hydrolase/hydrolase inhibitor
Title: Crystal structure of human sirt3 with elt inhibitor 3 [14-(4 [(methylsulfonyl)amino]ethyl}piperidin-1-yl)thieno[3,2-d]py 6-carboxamide]
Structure: NAD-dependent protein deacetylase sirtuin-3, mito chain: a. Fragment: unp residues 118-399. Synonym: hsirt3, regulatory protein sir2 homolog 3, sir2-li 3. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: sirt3, sir2l3. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
2.24Å     R-factor:   0.200     R-free:   0.247
Authors: H.Dai
Key ref: J.S.Disch et al. (2013). Discovery of thieno[3,2-d]pyrimidine-6-carboxamides as potent inhibitors of SIRT1, SIRT2, and SIRT3. J Med Chem, 56, 3666-3679. PubMed id: 23570514 DOI: 10.1021/jm400204k
Date:
22-Mar-13     Release date:   24-Apr-13    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q9NTG7  (SIR3_HUMAN) -  NAD-dependent protein deacetylase sirtuin-3, mitochondrial
Seq:
Struc:
399 a.a.
274 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     protein deacetylation   1 term 
  Biochemical function     hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides     4 terms  

 

 
DOI no: 10.1021/jm400204k J Med Chem 56:3666-3679 (2013)
PubMed id: 23570514  
 
 
Discovery of thieno[3,2-d]pyrimidine-6-carboxamides as potent inhibitors of SIRT1, SIRT2, and SIRT3.
J.S.Disch, G.Evindar, C.H.Chiu, C.A.Blum, H.Dai, L.Jin, E.Schuman, K.E.Lind, S.L.Belyanskaya, J.Deng, F.Coppo, L.Aquilani, T.L.Graybill, J.W.Cuozzo, S.Lavu, C.Mao, G.P.Vlasuk, R.B.Perni.
 
  ABSTRACT  
 
The sirtuins SIRT1, SIRT2, and SIRT3 are NAD(+) dependent deacetylases that are considered potential targets for metabolic, inflammatory, oncologic, and neurodegenerative disorders. Encoded library technology (ELT) was used to affinity screen a 1.2 million heterocycle enriched library of DNA encoded small molecules, which identified pan-inhibitors of SIRT1/2/3 with nanomolar potency (e.g., 11c: IC50 = 3.6, 2.7, and 4.0 nM for SIRT1, SIRT2, and SIRT3, respectively). Subsequent SAR studies to improve physiochemical properties identified the potent drug like analogues 28 and 31. Crystallographic studies of 11c, 28, and 31 bound in the SIRT3 active site revealed that the common carboxamide binds in the nicotinamide C-pocket and the aliphatic portions of the inhibitors extend through the substrate channel, explaining the observable SAR. These pan SIRT1/2/3 inhibitors, representing a novel chemotype, are significantly more potent than currently available inhibitors, which makes them valuable tools for sirtuin research.