5ACY

N-TERMINAL BROMODOMAIN OF HUMAN BRD4 WITH 1-(2R,4S)-2-methyl-4-(phenylamino)-6-4-(piperidin-1-ylmethyl)phenyl-1,2,3,4- tetrahydroquinolin-1-yl-ethan-1-one


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.01 Å
  • R-Value Free: 0.271 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.214 

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Literature

Autism-Like Syndrome is Induced by Pharmacological Suppression of Bet Proteins in Young Mice.

Sullivan, J.M.Badimon, A.Schaefer, U.Ayata, P.Gray, J.Chung, C.Von Schimmelmann, M.Zhang, F.Garton, N.Smithers, N.Lewis, H.Tarakhovsky, A.Prinjha, R.K.Schaefer, A.

(2015) J Exp Med 212: 1771

  • DOI: https://doi.org/10.1084/jem.20151271
  • Primary Citation of Related Structures:  
    5ACY

  • PubMed Abstract: 

    Studies investigating the causes of autism spectrum disorder (ASD) point to genetic, as well as epigenetic, mechanisms of the disease. Identification of epigenetic processes that contribute to ASD development and progression is of major importance and may lead to the development of novel therapeutic strategies. Here, we identify the bromodomain and extraterminal domain-containing proteins (BETs) as epigenetic regulators of genes involved in ASD-like behaviors in mice. We found that the pharmacological suppression of BET proteins in the brain of young mice, by the novel, highly specific, brain-permeable inhibitor I-BET858 leads to selective suppression of neuronal gene expression followed by the development of an autism-like syndrome. Many of the I-BET858-affected genes have been linked to ASD in humans, thus suggesting the key role of the BET-controlled gene network in the disorder. Our studies suggest that environmental factors controlling BET proteins or their target genes may contribute to the epigenetic mechanism of ASD.


  • Organizational Affiliation

    Department of Neuroscience and Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029 Department of Neuroscience and Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
BROMODOMAIN-CONTAINING PROTEIN 4
A, B
127Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for O60885 (Homo sapiens)
Explore O60885 
Go to UniProtKB:  O60885
PHAROS:  O60885
GTEx:  ENSG00000141867 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO60885
Sequence Annotations
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  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
9S3 Binding MOAD:  5ACY Kd: 6.4 (nM) from 1 assay(s)
BindingDB:  5ACY IC50: 398 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.01 Å
  • R-Value Free: 0.271 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.214 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.149α = 90
b = 59.497β = 90
c = 108.025γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
SCALAdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2015-10-07 
  • Deposition Author(s): Chung, C.

Revision History  (Full details and data files)

  • Version 1.0: 2015-10-07
    Type: Initial release
  • Version 1.1: 2015-11-04
    Changes: Database references