5D3L

First bromodomain of BRD4 bound to inhibitor XD35


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.50 Å
  • R-Value Free: 0.201 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.179 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

4-Acyl Pyrrole Derivatives Yield Novel Vectors for Designing Inhibitors of the Acetyl-Lysine Recognition Site of BRD4(1).

Hugle, M.Lucas, X.Weitzel, G.Ostrovskyi, D.Breit, B.Gerhardt, S.Einsle, O.Gunther, S.Wohlwend, D.

(2016) J Med Chem 59: 1518-1530

  • DOI: https://doi.org/10.1021/acs.jmedchem.5b01267
  • Primary Citation of Related Structures:  
    5D24, 5D25, 5D26, 5D3H, 5D3J, 5D3L, 5D3N, 5D3P, 5D3R, 5D3S, 5D3T

  • PubMed Abstract: 

    Several human diseases, including cancer, show altered signaling pathways resulting from changes in the activity levels of epigenetic modulators. In the past few years, small-molecule inhibitors against specific modulators, including the bromodomain and extra-terminal (BET) bromodomain family of acetylation readers, have shown early promise in the treatment of the genetically defined midline carcinoma and hematopoietic malignancies. We have recently developed a novel potent inhibitor of BET proteins, 1 (XD14[ Angew. Chem., Int. Ed. 2013, 52, 14055]), which exerts a strong inhibitory potential on the proliferation of specific leukemia cell lines. In the study presented here, we designed analogues of 1 to study the potential of substitutions on the 4-acyl pyrrole backbone to occupy additional sites within the substrate recognition site of BRD4(1). The compounds were profiled using ITC, DSF, and X-ray crystallography. We could introduce several substitutions that address previously untargeted areas of the substrate recognition site. This work may substantially contribute to the development of therapeutics with increased target specificity against BRD4-related malignancies.


  • Organizational Affiliation

    Institut für Biochemie, Albert-Ludwigs-Universität Freiburg , Albertstrasse 21, D-79104 Freiburg, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bromodomain-containing protein 4127Homo sapiensMutation(s): 1 
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
57F
Query on 57F

Download Ideal Coordinates CCD File 
B [auth A]4-acetyl-N-[5-(diethylsulfamoyl)-2-hydroxy-4-methylphenyl]-3-ethyl-5-methyl-1H-pyrrole-2-carboxamide
C21 H29 N3 O5 S
CGYOKHBJOYVFIV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
57F Binding MOAD:  5D3L Kd: 880 (nM) from 1 assay(s)
BindingDB:  5D3L Kd: 880 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.50 Å
  • R-Value Free: 0.201 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.179 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.58α = 90
b = 47.94β = 90
c = 58.32γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
SCALAdata scaling
PHASERphasing
iMOSFLMdata reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
German Research FoundationGermanyWO2012/1-1

Revision History  (Full details and data files)

  • Version 1.0: 2016-01-20
    Type: Initial release
  • Version 1.1: 2016-03-09
    Changes: Database references
  • Version 1.2: 2017-09-06
    Changes: Author supporting evidence