8QAL | pdb_00008qal

Crystal Structure of the first bromodomain of BRD4 in complex with acetyl-pyrrole derivative compound 83

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.30 Å
  • R-Value Free: 
    0.171 (Depositor), 0.179 (DCC) 
  • R-Value Work: 
    0.146 (Depositor), 0.156 (DCC) 
  • R-Value Observed: 
    0.147 (Depositor) 

Starting Model: experimental
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Literature

Enhanced cellular death in liver and breast cancer cells by dual BET/BRPF1 inhibitors.

Cazzanelli, G., Dalle Vedove, A., Sbardellati, N., Valer, L., Caflisch, A., Lolli, G.

(2024) Protein Sci 33: e5191-e5191

  • DOI: https://doi.org/10.1002/pro.5191
  • Primary Citation of Related Structures:  
    8QAL, 8QAN, 8QAP, 8QAR, 8QAZ, 8QB0, 8QB2

  • PubMed Abstract: 

    The acetylpyrrole scaffold is an acetylated lysine mimic that has been previously explored to develop bromodomain inhibitors. When tested on the hepatoma cell line Huh7 and the breast cancer cell line MDA-MB-231, a few compounds in our acetylpyrrole-thiazole library induced peculiar morphological changes, progressively causing cell death at increasing concentrations. Their evaluation on a panel of human bromodomains revealed concurrent inhibition of BRPF1 and BET bromodomains. To dissect the observed cellular effects, the acetylpyrrole derivatives were compared to JQ1 and GSK6853, chemical probes for the bromodomains of BET and BRPF1, respectively. The appearance of neurite-like extrusions, accompanied by βIII-tubulin overexpression, is caused by BET inhibition, with limited effect on cellular viability. Conversely, interference with BRPF1 induces cellular death but not phenotypic alterations. Combined treatment with JQ1 and GSK6853 showed additivity in reducing cellular viability, comparably to the acetylpyrrole-thiazole-based BET/BRPF1 inhibitors. In addition, we determined the crystallographic structures of the BRD4 and BRPF1 bromodomains in complex with the acetylpyrrole-thiazole compounds. The binding modes in the two bromodomains show similar interactions for the acetylpyrrole and different orientations of the moiety that point to the rim of the acetyl-lysine pocket.

    • Organizational Affiliation: 

    Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, Trento, Italy.


Macromolecules
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(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bromodomain-containing protein 4127Homo sapiensMutation(s): 0 
Gene Names: BRD4, HUNK1
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
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.30 Å
  • R-Value Free:  0.171 (Depositor), 0.179 (DCC) 
  • R-Value Work:  0.146 (Depositor), 0.156 (DCC) 
  • R-Value Observed: 0.147 (Depositor) 
Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 37.213α = 90
b = 44.668β = 90
c = 77.734γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing

Structure Validation

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Entry History & Funding Information

Deposition Data

Funding OrganizationLocationGrant Number
Italian Association for Cancer ResearchItalyMFAG 2017 - ID. 19882

Revision History  (Full details and data files)

  • Version 1.0: 2024-09-11
    Type: Initial release
  • Version 1.1: 2025-03-26
    Changes: Database references, Structure summary