4JT9

Crystal Structure of human SIRT3 with ELT inhibitor 3 [14-(4-{2-[(methylsulfonyl)amino]ethyl}piperidin-1-yl)thieno[3,2-d]pyrimidine-6-carboxamide]


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.24 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.197 
  • R-Value Observed: 0.200 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of Thieno[3,2-d]pyrimidine-6-carboxamides as Potent Inhibitors of SIRT1, SIRT2, and SIRT3.

Disch, J.S.Evindar, G.Chiu, C.H.Blum, C.A.Dai, H.Jin, L.Schuman, E.Lind, K.E.Belyanskaya, S.L.Deng, J.Coppo, F.Aquilani, L.Graybill, T.L.Cuozzo, J.W.Lavu, S.Mao, C.Vlasuk, G.P.Perni, R.B.

(2013) J Med Chem 56: 3666-3679

  • DOI: https://doi.org/10.1021/jm400204k
  • Primary Citation of Related Structures:  
    4JSR, 4JT8, 4JT9

  • PubMed 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.


  • Organizational Affiliation

    Sirtris a GSK Company, Cambridge, Massachusetts, United States. jdisch92@gmail.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
NAD-dependent protein deacetylase sirtuin-3, mitochondrial285Homo sapiensMutation(s): 0 
Gene Names: SIRT3SIR2L3
EC: 3.5.1
UniProt & NIH Common Fund Data Resources
Find proteins for Q9NTG7 (Homo sapiens)
Explore Q9NTG7 
Go to UniProtKB:  Q9NTG7
PHAROS:  Q9NTG7
GTEx:  ENSG00000142082 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9NTG7
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
1NS BindingDB:  4JT9 IC50: 7.2 (nM) from 1 assay(s)
PDBBind:  4JT9 IC50: 7.2 (nM) from 1 assay(s)
Binding MOAD:  4JT9 IC50: 7.2 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.24 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.197 
  • R-Value Observed: 0.200 
  • Space Group: P 65
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 120.464α = 90
b = 120.464β = 90
c = 44.468γ = 120
Software Package:
Software NamePurpose
REFMACrefinement

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2013-04-24 
  • Deposition Author(s): Dai, H.

Revision History  (Full details and data files)

  • Version 1.0: 2013-04-24
    Type: Initial release
  • Version 1.1: 2013-07-03
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations