6ZS3 | pdb_00006zs3

Crystal structure of the fifth bromodomain of human protein polybromo-1 in complex with 2-(6-amino-5-(piperazin-1-yl)pyridazin-3-yl)phenol


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.67 Å
  • R-Value Free: 
    0.243 (Depositor), 0.250 (DCC) 
  • R-Value Work: 
    0.211 (Depositor), 0.210 (DCC) 
  • R-Value Observed: 
    0.213 (Depositor) 

Starting Model: experimental
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Ligand Structure Quality Assessment 

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This is version 1.2 of the entry. See complete history


Literature

Pan-SMARCA/PB1 Bromodomain Inhibitors and Their Role in Regulating Adipogenesis.

Wanior, M.Preuss, F.Ni, X.Kramer, A.Mathea, S.Gobel, T.Heidenreich, D.Simonyi, S.Kahnt, A.S.Joerger, A.C.Knapp, S.

(2020) J Med Chem 63: 14680-14699

  • DOI: https://doi.org/10.1021/acs.jmedchem.0c01242
  • Primary Citation of Related Structures:  
    6ZN6, 6ZNV, 6ZS2, 6ZS3, 6ZS4

  • PubMed Abstract: 

    Accessibility of the human genome is modulated by the ATP-driven SWI/SNF chromatin remodeling multiprotein complexes BAF (BRG1/BRM-associated factor) and PBAF (polybromo-associated BAF factor), which involves reading of acetylated histone tails by the bromodomain-containing proteins SMARCA2 (BRM), SMARCA4 (BRG1), and polybromo-1. Dysregulation of chromatin remodeling leads to aberrant cell proliferation and differentiation. Here, we have characterized a set of potent and cell-active bromodomain inhibitors with pan-selectivity for canonical family VIII bromodomains. Targeted SWI/SNF bromodomain inhibition blocked the expression of key genes during adipogenesis, including the transcription factors PPARγ and C/EBPα, and impaired the differentiation of 3T3-L1 murine fibroblasts into adipocytes. Our data highlight the role of SWI/SNF bromodomains in adipogenesis and provide a framework for the development of SWI/SNF bromodomain inhibitors for indirect targeting of key transcription factors regulating cell differentiation.


  • Organizational Affiliation

    Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Protein polybromo-1
A, B
124Homo sapiensMutation(s): 0 
Gene Names: PBRM1BAF180PB1
UniProt & NIH Common Fund Data Resources
Find proteins for Q86U86 (Homo sapiens)
Explore Q86U86 
Go to UniProtKB:  Q86U86
PHAROS:  Q86U86
GTEx:  ENSG00000163939 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ86U86
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.67 Å
  • R-Value Free:  0.243 (Depositor), 0.250 (DCC) 
  • R-Value Work:  0.211 (Depositor), 0.210 (DCC) 
  • R-Value Observed: 0.213 (Depositor) 
Space Group: I 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 56.18α = 90
b = 41.19β = 96.347
c = 133.907γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted FX5Click on this verticalbar to view details

Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2020-10-07
    Type: Initial release
  • Version 1.1: 2021-05-05
    Changes: Database references
  • Version 1.2: 2024-01-31
    Changes: Data collection, Database references, Refinement description