4HBX

Crystal Structure of the first bromodomain of human BRD4 in complex with a quinazolin ligand


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.62 Å
  • R-Value Free: 0.210 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.179 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Identification of a Chemical Probe for Bromo and Extra C-Terminal Bromodomain Inhibition through Optimization of a Fragment-Derived Hit.

Fish, P.V.Filippakopoulos, P.Bish, G.Brennan, P.E.Bunnage, M.E.Cook, A.S.Federov, O.Gerstenberger, B.S.Jones, H.Knapp, S.Marsden, B.Nocka, K.Owen, D.R.Philpott, M.Picaud, S.Primiano, M.J.Ralph, M.J.Sciammetta, N.Trzupek, J.D.

(2012) J Med Chem 55: 9831-9837

  • DOI: https://doi.org/10.1021/jm3010515
  • Primary Citation of Related Structures:  
    4E96, 4HBV, 4HBW, 4HBX, 4HBY

  • PubMed Abstract: 

    The posttranslational modification of chromatin through acetylation at selected histone lysine residues is governed by histone acetyltransferases (HATs) and histone deacetylases (HDACs). The significance of this subset of the epigenetic code is interrogated and interpreted by an acetyllysine-specific protein-protein interaction with bromodomain reader modules. Selective inhibition of the bromo and extra C-terminal domain (BET) family of bromodomains with a small molecule is feasible, and this may represent an opportunity for disease intervention through the recently disclosed antiproliferative and anti-inflammatory properties of such inhibitors. Herein, we describe the discovery and structure-activity relationship (SAR) of a novel, small-molecule chemical probe for BET family inhibition that was identified through the application of structure-based fragment assessment and optimization techniques. This has yielded a potent, selective compound with cell-based activity (PFI-1) that may further add to the understanding of BET family function within the bromodomains.


  • Organizational Affiliation

    Pfizer Worldwide Medicinal Chemistry, Pfizer Worldwide R&D , Ramsgate Road, Sandwich CT13 9NJ, United Kingdom.


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 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
14X
Query on 14X

Download Ideal Coordinates CCD File 
B [auth A]3-methyl-6-(pyrrolidin-1-ylsulfonyl)-3,4-dihydroquinazolin-2(1H)-one
C13 H17 N3 O3 S
JPBCSPCBFLTTPI-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
14X PDBBind:  4HBX IC50: 1900 (nM) from 1 assay(s)
Binding MOAD:  4HBX IC50: 1900 (nM) from 1 assay(s)
BindingDB:  4HBX IC50: 4800 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.62 Å
  • R-Value Free: 0.210 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.179 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 43.48α = 90
b = 48.37β = 90
c = 61.03γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction
CrystalCleardata collection
MOSFLMdata reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2012-10-31
    Type: Initial release
  • Version 1.1: 2012-11-14
    Changes: Database references
  • Version 1.2: 2012-12-12
    Changes: Database references
  • Version 1.3: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description