5Y5N

Crystal structure of human Sirtuin 2 in complex with a selective inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.256 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Potent mechanism-based sirtuin-2-selective inhibition by anin situ-generated occupant of the substrate-binding site, "selectivity pocket" and NAD+-binding site.

Mellini, P.Itoh, Y.Tsumoto, H.Li, Y.Suzuki, M.Tokuda, N.Kakizawa, T.Miura, Y.Takeuchi, J.Lahtela-Kakkonen, M.Suzuki, T.

(2017) Chem Sci 8: 6400-6408

  • DOI: https://doi.org/10.1039/c7sc02738a
  • Primary Citation of Related Structures:  
    5Y5N

  • PubMed Abstract: 

    Sirtuin 2 (SIRT2), a member of the NAD + -dependent histone deacetylase family, has recently received increasing attention due to its potential involvement in neurodegenerative diseases and the progression of cancer. Potent and selective SIRT2 inhibitors thus represent desirable biological probes. Based on the X-ray crystal structure of SIRT2 in complex with a previously reported weak inhibitor ( 6 ), we identified in this study the potent mechanism-based inactivator KPM-2 ( 36 ), which is selective toward SIRT2. Compound 36 engages in a nucleophilic attack toward NAD + at the active site of SIRT2, which affords a stable 36 -ADP-ribose conjugate that simultaneously occupies the substrate-binding site, the "selectivity pocket" and the NAD + -binding site. Moreover, 36 exhibits antiproliferative activity in cancer cells and remarkable neurite outgrowth activity. This strategy for the selective inhibition of SIRT2 should allow further probing of the biology of SIRT2, and promote the development of new disease treatment strategies.


  • Organizational Affiliation

    Graduate School of Medical Science , Kyoto Prefectural University of Medicine , 1-5 Shimogamohangi-cho, Sakyo-ku , Kyoto 606-0823 , Japan . Email: suzukit@koto.kpu-m.ac.jp.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
NAD-dependent protein deacetylase sirtuin-2336Homo 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
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
8NO
Query on 8NO

Download Ideal Coordinates CCD File 
C [auth A]2-[[3-(2-phenylethoxy)phenyl]amino]benzamide
C21 H20 N2 O2
VVRUXFPJOVUDCV-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
B [auth A]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
8NO BindingDB:  5Y5N IC50: min: 1000, max: 1740 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.256 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 50.85α = 90
b = 57.98β = 90
c = 124.532γ = 90
Software Package:
Software NamePurpose
DENZOdata collection
SCALEPACKdata scaling
MOLREPphasing
CNXrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-09-06
    Type: Initial release
  • Version 1.1: 2019-12-18
    Changes: Database references
  • Version 1.2: 2023-11-22
    Changes: Data collection, Database references, Refinement description