6MH1

CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH HU-10, A 1,4,5-Trisubstituted Imidazole Analogue


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.202 
  • R-Value Work: 0.159 
  • R-Value Observed: 0.161 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Molecular Basis for the N-Terminal Bromodomain-and-Extra-Terminal-Family Selectivity of a Dual Kinase-Bromodomain Inhibitor.

Divakaran, A.Talluri, S.K.Ayoub, A.M.Mishra, N.K.Cui, H.Widen, J.C.Berndt, N.Zhu, J.Y.Carlson, A.S.Topczewski, J.J.Schonbrunn, E.K.Harki, D.A.Pomerantz, W.C.K.

(2018) J Med Chem 61: 9316-9334

  • DOI: https://doi.org/10.1021/acs.jmedchem.8b01248
  • Primary Citation of Related Structures:  
    6MH1, 6MH7

  • PubMed Abstract: 

    As regulators of transcription, epigenetic proteins that interpret post-translational modifications to N-terminal histone tails are essential for maintaining cellular homeostasis. When dysregulated, "reader" proteins become drivers of disease. In the case of bromodomains, which recognize N-ε-acetylated lysine, selective inhibition of individual bromodomain-and-extra-terminal (BET)-family bromodomains has proven challenging. We describe the >55-fold N-terminal-BET bromodomain selectivity of 1,4,5-trisubstituted-imidazole dual kinase-bromodomain inhibitors. Selectivity for the BRD4 N-terminal bromodomain (BRD4(1)) over its second bromodomain (BRD4(2)) arises from the displacement of ordered waters and the conformational flexibility of lysine-141 in BRD4(1). Cellular efficacy was demonstrated via reduction of c-Myc expression, inhibition of NF-κB signaling, and suppression of IL-8 production through potential synergistic inhibition of BRD4(1) and p38α. These dual inhibitors provide a new scaffold for domain-selective inhibition of BRD4, the aberrant function of which plays a key role in cancer and inflammatory signaling.


  • Organizational Affiliation

    Department of Medicinal Chemistry , University of Minnesota , 2231 6th Street SE , Minneapolis , Minnesota 55455 , United States.


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 
Gene Names: BRD4HUNK1
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
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.202 
  • R-Value Work: 0.159 
  • R-Value Observed: 0.161 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.83α = 90
b = 59.51β = 90
c = 111.42γ = 90
Software Package:
Software NamePurpose
XDSdata reduction
XSCALEdata scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACTdata extraction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Science Foundation (NSF, United States)United StatesCHE-1352019
American Heart AssociationUnited States15SDG25710427

Revision History  (Full details and data files)

  • Version 1.0: 2019-08-07
    Type: Initial release
  • Version 1.1: 2019-11-27
    Changes: Author supporting evidence
  • Version 1.2: 2024-03-13
    Changes: Data collection, Database references