5TI5

CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH INHIBITOR 8841880


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.83 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.164 
  • R-Value Observed: 0.167 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Identification of a Novel Class of BRD4 Inhibitors by Computational Screening and Binding Simulations.

Allen, B.K.Mehta, S.Ember, S.W.J.Zhu, J.Y.Schonbrunn, E.Ayad, N.G.Schurer, S.C.

(2017) ACS Omega 2: 4760-4771

  • DOI: https://doi.org/10.1021/acsomega.7b00553
  • Primary Citation of Related Structures:  
    5TI2, 5TI3, 5TI4, 5TI5, 5TI6, 5TI7

  • PubMed Abstract: 

    Computational screening is a method to prioritize small-molecule compounds based on the structural and biochemical attributes built from ligand and target information. Previously, we have developed a scalable virtual screening workflow to identify novel multitarget kinase/bromodomain inhibitors. In the current study, we identified several novel N -[3-(2-oxo-pyrrolidinyl)phenyl]-benzenesulfonamide derivatives that scored highly in our ensemble docking protocol. We quantified the binding affinity of these compounds for BRD4(BD1) biochemically and generated cocrystal structures, which were deposited in the Protein Data Bank. As the docking poses obtained in the virtual screening pipeline did not align with the experimental cocrystal structures, we evaluated the predictions of their precise binding modes by performing molecular dynamics (MD) simulations. The MD simulations closely reproduced the experimentally observed protein-ligand cocrystal binding conformations and interactions for all compounds. These results suggest a computational workflow to generate experimental-quality protein-ligand binding models, overcoming limitations of docking results due to receptor flexibility and incomplete sampling, as a useful starting point for the structure-based lead optimization of novel BRD4(BD1) inhibitors.


  • Organizational Affiliation

    Department of Molecular and Cellular Pharmacology, Miller School of Medicine, Center for Computational Science, Center for Therapeutic Innovation Miller School of Medicine, Miami Project to Cure Paralysis, Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida 33136, United States.


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
Binding Affinity Annotations 
IDSourceBinding Affinity
7CN Binding MOAD:  5TI5 IC50: 4.10e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.83 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.164 
  • R-Value Observed: 0.167 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 35.12α = 90
b = 46.51β = 90
c = 77.83γ = 90
Software Package:
Software NamePurpose
XSCALEdata scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Cancer Institute (NIH/NCI)United StatesU54CA189205
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)United StatesU54HL127624
NGAUnited StatesNS067289

Revision History  (Full details and data files)

  • Version 1.0: 2017-08-09
    Type: Initial release
  • Version 1.1: 2017-09-13
    Changes: Author supporting evidence
  • Version 1.2: 2017-09-20
    Changes: Database references
  • Version 1.3: 2019-12-04
    Changes: Author supporting evidence
  • Version 1.4: 2024-03-06
    Changes: Data collection, Database references