4XY9

Crystal Structure of the first bromodomain of human BRD4 in complex with a 2-amine-9H-purine ligand


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.83 Å
  • R-Value Free: 0.206 
  • R-Value Work: 0.157 
  • R-Value Observed: 0.160 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

9H-Purine Scaffold Reveals Induced-Fit Pocket Plasticity of the BRD9 Bromodomain.

Picaud, S.Strocchia, M.Terracciano, S.Lauro, G.Mendez, J.Daniels, D.L.Riccio, R.Bifulco, G.Bruno, I.Filippakopoulos, P.

(2015) J Med Chem 58: 2718-2736

  • DOI: https://doi.org/10.1021/jm501893k
  • Primary Citation of Related Structures:  
    4XY8, 4XY9, 4XYA

  • PubMed Abstract: 

    The 2-amine-9H-purine scaffold was identified as a weak bromodomain template and was developed via iterative structure based design into a potent nanomolar ligand for the bromodomain of human BRD9 with small residual micromolar affinity toward the bromodomain of BRD4. Binding of the lead compound 11 to the bromodomain of BRD9 results in an unprecedented rearrangement of residues forming the acetyllysine recognition site, affecting plasticity of the protein in an induced-fit pocket. The compound does not exhibit any cytotoxic effect in HEK293 cells and displaces the BRD9 bromodomain from chromatin in bioluminescence proximity assays without affecting the BRD4/histone complex. The 2-amine-9H-purine scaffold represents a novel template that can be further modified to yield highly potent and selective tool compounds to interrogate the biological role of BRD9 in diverse cellular systems.


  • Organizational Affiliation

    †Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.


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
43U
Query on 43U

Download Ideal Coordinates CCD File 
C [auth A]6-(5-bromo-2-methoxyphenyl)-9H-purin-2-amine
C12 H10 Br N5 O
KDNVOUMYSICLPF-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
43U Binding MOAD:  4XY9 Kd: 4651 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.83 Å
  • R-Value Free: 0.206 
  • R-Value Work: 0.157 
  • R-Value Observed: 0.160 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 36.915α = 90
b = 44.229β = 90
c = 79.584γ = 90
Software Package:
Software NamePurpose
PROTEUM PLUSdata reduction
PROTEUM PLUSdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Wellcome TrustUnited Kingdom095751/Z/11/Z

Revision History  (Full details and data files)

  • Version 1.0: 2015-03-11
    Type: Initial release
  • Version 1.1: 2015-03-18
    Changes: Database references
  • Version 1.2: 2015-04-08
    Changes: Database references