4RMH

Human Sirt2 in complex with SirReal2 and Ac-Lys-H3 peptide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.42 Å
  • R-Value Free: 0.188 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.181 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Selective Sirt2 inhibition by ligand-induced rearrangement of the active site.

Rumpf, T.Schiedel, M.Karaman, B.Roessler, C.North, B.J.Lehotzky, A.Olah, J.Ladwein, K.I.Schmidtkunz, K.Gajer, M.Pannek, M.Steegborn, C.Sinclair, D.A.Gerhardt, S.Ovadi, J.Schutkowski, M.Sippl, W.Einsle, O.Jung, M.

(2015) Nat Commun 6: 6263-6263

  • DOI: https://doi.org/10.1038/ncomms7263
  • Primary Citation of Related Structures:  
    4RMG, 4RMH, 4RMI, 4RMJ

  • PubMed Abstract: 

    Sirtuins are a highly conserved class of NAD(+)-dependent lysine deacylases. The human isotype Sirt2 has been implicated in the pathogenesis of cancer, inflammation and neurodegeneration, which makes the modulation of Sirt2 activity a promising strategy for pharmaceutical intervention. A rational basis for the development of optimized Sirt2 inhibitors is lacking so far. Here we present high-resolution structures of human Sirt2 in complex with highly selective drug-like inhibitors that show a unique inhibitory mechanism. Potency and the unprecedented Sirt2 selectivity are based on a ligand-induced structural rearrangement of the active site unveiling a yet-unexploited binding pocket. Application of the most potent Sirtuin-rearranging ligand, termed SirReal2, leads to tubulin hyperacetylation in HeLa cells and induces destabilization of the checkpoint protein BubR1, consistent with Sirt2 inhibition in vivo. Our structural insights into this unique mechanism of selective sirtuin inhibition provide the basis for further inhibitor development and selective tools for sirtuin biology.


  • Organizational Affiliation

    Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg, Albertstraße 25, 79104 Freiburg im Breisgau, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
NAD-dependent protein deacetylase sirtuin-2304Homo sapiensMutation(s): 0 
Gene Names: SIRT2SIR2LSIR2L2
EC: 3.5.1
UniProt & NIH Common Fund Data Resources
Find proteins for Q8IXJ6 (Homo sapiens)
Explore Q8IXJ6 
Go to UniProtKB:  Q8IXJ6
PHAROS:  Q8IXJ6
GTEx:  ENSG00000068903 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ8IXJ6
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Ac-Lys-H3 peptide7N/AMutation(s): 0 
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
3TE
Query on 3TE

Download Ideal Coordinates CCD File 
D [auth A]2-[(4,6-dimethylpyrimidin-2-yl)sulfanyl]-N-[5-(naphthalen-1-ylmethyl)-1,3-thiazol-2-yl]acetamide
C22 H20 N4 O S2
MENNDDDTIIZDDN-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
C [auth A]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
ALY
Query on ALY
B
L-PEPTIDE LINKINGC8 H16 N2 O3LYS
Binding Affinity Annotations 
IDSourceBinding Affinity
3TE BindingDB:  4RMH IC50: min: 140, max: 1.00e+4 (nM) from 10 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.42 Å
  • R-Value Free: 0.188 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.181 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 35.994α = 90
b = 73.302β = 95.23
c = 55.291γ = 90
Software Package:
Software NamePurpose
PHASERphasing
REFMACrefinement
XDSdata reduction
Aimlessdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2015-02-25
    Type: Initial release
  • Version 1.1: 2024-02-28
    Changes: Data collection, Database references, Derived calculations