3U5L

Crystal Structure of the first bromodomain of human BRD4 in complex with a benzo-triazepine ligand (BzT-7)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.39 Å
  • R-Value Free: 0.142 
  • R-Value Work: 0.111 
  • R-Value Observed: 0.112 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Benzodiazepines and benzotriazepines as protein interaction inhibitors targeting bromodomains of the BET family.

Filippakopoulos, P.Picaud, S.Fedorov, O.Keller, M.Wrobel, M.Morgenstern, O.Bracher, F.Knapp, S.

(2012) Bioorg Med Chem 20: 1878-1886

  • DOI: https://doi.org/10.1016/j.bmc.2011.10.080
  • Primary Citation of Related Structures:  
    3U5J, 3U5K, 3U5L

  • PubMed Abstract: 

    Benzodiazepines are psychoactive drugs with anxiolytic, sedative, skeletal muscle relaxant and amnestic properties. Recently triazolo-benzodiazepines have been also described as potent and highly selective protein interaction inhibitors of bromodomain and extra-terminal (BET) proteins, a family of transcriptional co-regulators that play a key role in cancer cell survival and proliferation, but the requirements for high affinity interaction of this compound class with bromodomains has not been described. Here we provide insight into the structure-activity relationship (SAR) and selectivity of this versatile scaffold. In addition, using high resolution crystal structures we compared the binding mode of a series of benzodiazepine (BzD) and related triazolo-benzotriazepines (BzT) derivatives including clinically approved drugs such as alprazolam and midazolam. Our analysis revealed the importance of the 1-methyl triazolo ring system for BET binding and suggests modifications for the development of further high affinity bromodomain inhibitors.


  • Organizational Affiliation

    University of Oxford, Nuffield Department of Clinical Medicine, Structural Genomics Consortium, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7LD, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bromodomain-containing protein 4127Homo 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
08K
Query on 08K

Download Ideal Coordinates CCD File 
C [auth A]8-chloro-1,4-dimethyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,3,4]benzotriazepine
C17 H14 Cl N5
UYIVCPRWMLOCSB-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
B [auth A]1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
08K Binding MOAD:  3U5L Kd: 640 (nM) from 1 assay(s)
PDBBind:  3U5L Kd: 640 (nM) from 1 assay(s)
BindingDB:  3U5L Kd: 640 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.39 Å
  • R-Value Free: 0.142 
  • R-Value Work: 0.111 
  • R-Value Observed: 0.112 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 37.36α = 90
b = 44.13β = 90
c = 78.38γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction
DNAdata collection
XDSdata reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2011-11-23
    Type: Initial release
  • Version 1.1: 2012-03-07
    Changes: Database references
  • Version 1.2: 2012-03-21
    Changes: Database references
  • Version 1.3: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description