3MU6

Inhibiting the Binding of Class IIa Histone Deacetylases to Myocyte Enhancer Factor-2 by Small Molecules


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.43 Å
  • R-Value Free: 0.251 
  • R-Value Work: 0.230 
  • R-Value Observed: 0.231 

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Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

Inhibition of the function of class IIa HDACs by blocking their interaction with MEF2.

Jayathilaka, N.Han, A.Gaffney, K.J.Dey, R.Jarusiewicz, J.A.Noridomi, K.Philips, M.A.Lei, X.He, J.Ye, J.Gao, T.Petasis, N.A.Chen, L.

(2012) Nucleic Acids Res 40: 5378-5388

  • DOI: https://doi.org/10.1093/nar/gks189
  • Primary Citation of Related Structures:  
    3MU6

  • PubMed Abstract: 

    Enzymes that modify the epigenetic status of cells provide attractive targets for therapy in various diseases. The therapeutic development of epigenetic modulators, however, has been largely limited to direct targeting of catalytic active site conserved across multiple members of an enzyme family, which complicates mechanistic studies and drug development. Class IIa histone deacetylases (HDACs) are a group of epigenetic enzymes that depends on interaction with Myocyte Enhancer Factor-2 (MEF2) for their recruitment to specific genomic loci. Targeting this interaction presents an alternative approach to inhibiting this class of HDACs. We have used structural and functional approaches to identify and characterize a group of small molecules that indirectly target class IIa HDACs by blocking their interaction with MEF2 on DNA.Weused X-ray crystallography and (19)F NMRto show that these compounds directly bind to MEF2. We have also shown that the small molecules blocked the recruitment of class IIa HDACs to MEF2-targeted genes to enhance the expression of those targets. These compounds can be used as tools to study MEF2 and class IIa HDACs in vivo and as leads for drug development.


  • Organizational Affiliation

    Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA. jayathil@usc.edu


Macromolecules

Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Myocyte-specific enhancer factor 2AA,
B,
E [auth C],
F [auth D]
71Homo sapiensMutation(s): 1 
Gene Names: MEF2AMEF2
UniProt & NIH Common Fund Data Resources
Find proteins for Q02078 (Homo sapiens)
Explore Q02078 
Go to UniProtKB:  Q02078
PHAROS:  Q02078
GTEx:  ENSG00000068305 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ02078
Sequence Annotations
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  • Reference Sequence

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Entity ID: 2
MoleculeChains LengthOrganismImage
DNA (5'-D(*AP*AP*AP*GP*CP*TP*AP*TP*TP*AP*TP*TP*AP*GP*CP*TP*T)-3')C [auth E],
G
17N/A
Sequence Annotations
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  • Reference Sequence

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Entity ID: 3
MoleculeChains LengthOrganismImage
DNA (5'-D(*TP*AP*AP*GP*CP*TP*AP*AP*TP*AP*AP*TP*AP*GP*CP*TP*T)-3')D [auth F],
H
17N/A
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
BXL
Query on BXL

Download Ideal Coordinates CCD File 
I [auth A](3E)-N~8~-(2-aminophenyl)-N~1~-phenyloct-3-enediamide
C20 H23 N3 O2
WWKBRKDVEBSJBW-LZCJLJQNSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.43 Å
  • R-Value Free: 0.251 
  • R-Value Work: 0.230 
  • R-Value Observed: 0.231 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.567α = 114.12
b = 61.622β = 89.99
c = 61.478γ = 89.95
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACTdata extraction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-11-02
    Type: Initial release
  • Version 1.1: 2012-02-22
    Changes: Database references
  • Version 1.2: 2012-03-21
    Changes: Database references
  • Version 1.3: 2012-07-25
    Changes: Database references
  • Version 1.4: 2017-11-08
    Changes: Refinement description
  • Version 1.5: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description