6AJZ

Joint nentron and X-ray structure of BRD4 in complex with colchicin


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.30 Å
  • R-Value Free: 0.179 
  • R-Value Work: 0.163 
  • R-Value Observed: 0.164 

  • Method: NEUTRON DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.205 

wwPDB Validation   3D Report Full Report


This is version 1.0 of the entry. See complete history


Literature

Structural and thermodynamic characterization of the binding of isoliquiritigenin to the first bromodomain of BRD4.

Yokoyama, T.Matsumoto, K.Ostermann, A.Schrader, T.E.Nabeshima, Y.Mizuguchi, M.

(2019) FEBS J 286: 1656-1667

  • DOI: https://doi.org/10.1111/febs.14736
  • Primary Citation of Related Structures:  
    6AJV, 6AJW, 6AJX, 6AJY, 6AJZ

  • PubMed Abstract: 

    Bromodomain-containing protein 4 (BRD4) recognizes the acetylated lysine of histone H4 via its bromodomains, leading to the recruitment of positive transcription elongation factor b. Small molecules that inhibit BRD4 have potential as anticancer agents by leading to the downregulation of specific oncogenes. Using X-ray crystallographic screening, we identified the BRD4 inhibitory activity of isoliquiritigenin (ISL), a natural chalcone found in licorice. Structural analysis revealed that ISL bound to BRD4 with a novel binding mode and squeezed out one of the six conserved water molecules that form a strong hydrogen bond network. The thermodynamic analysis revealed that the binding of ISL is enthalpy driven, suggesting that strong hydrogen bonds would compensate for the desolvation penalty. Neutron protein crystallography further suggested that the favorable binding enthalpy originates from the stabilization and optimization of the hydrogen bond network of the conserved water molecules. Here, we describe the novelty and potential of ISL as a template for new BRD4 inhibitors.


  • Organizational Affiliation

    Faculty of Pharmaceutical Sciences, University of Toyama, Japan.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bromodomain-containing protein 4135Homo 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
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
LOC (Subject of Investigation/LOI)
Query on LOC

Download Ideal Coordinates CCD File 
B [auth A]N-[(7S)-1,2,3,10-tetramethoxy-9-oxo-6,7-dihydro-5H-benzo[d]heptalen-7-yl]ethanamide
C22 H25 N O6
IAKHMKGGTNLKSZ-INIZCTEOSA-N
NA
Query on NA

Download Ideal Coordinates CCD File 
C [auth A]SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.30 Å
  • R-Value Free: 0.179 
  • R-Value Work: 0.163 
  • R-Value Observed: 0.164 
  • Space Group: P 21 21 21
  • Method: NEUTRON DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.205 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 36.763α = 90
b = 47.101β = 90
c = 79.052γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
HKL-2000data reduction
XSCALEdata scaling
SCALEPACKdata scaling
MOLREPphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-06-12
    Type: Initial release