7LAH

Crystal structure of the first bromodomain (BD1) of human BRD2 bound to bromosporine


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.206 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.181 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Differential BET Bromodomain Inhibition by Dihydropteridinone and Pyrimidodiazepinone Kinase Inhibitors.

Karim, R.M.Bikowitz, M.J.Chan, A.Zhu, J.Y.Grassie, D.Becker, A.Berndt, N.Gunawan, S.Lawrence, N.J.Schonbrunn, E.

(2021) J Med Chem 64: 15772-15786

  • DOI: https://doi.org/10.1021/acs.jmedchem.1c01096
  • Primary Citation of Related Structures:  
    5V67, 5VBO, 5VBP, 5VBQ, 5VBR, 7BJY, 7K6G, 7K6H, 7KO0, 7L6D, 7L72, 7L73, 7L9G, 7L9J, 7L9K, 7L9L, 7LAH, 7LAI, 7LAJ, 7LAK, 7LAU, 7LAY, 7LAZ, 7LB4, 7LBT, 7LEJ, 7LEK, 7LEL, 7LEM

  • PubMed Abstract: 

    BRD4 and other members of the bromodomain and extraterminal (BET) family of proteins are promising epigenetic targets for the development of novel therapeutics. Among the reported BRD4 inhibitors are dihydropteridinones and benzopyrimidodiazepinones originally designed to target the kinases PLK1, ERK5, and LRRK2. While these kinase inhibitors were identified as BRD4 inhibitors, little is known about their binding potential and structural details of interaction with the other BET bromodomains. We comprehensively characterized a series of known and newly identified dual BRD4-kinase inhibitors against all eight individual BET bromodomains. A detailed analysis of 23 novel cocrystal structures of BET-kinase inhibitor complexes in combination with direct binding assays and cell signaling studies revealed significant differences in molecular shape complementarity and inhibitory potential. Collectively, the data offer new insights into the action of kinase inhibitors across BET bromodomains, which may aid the development of drugs to inhibit certain BET proteins and kinases differentially.


  • Organizational Affiliation

    Drug Discovery Department, Moffitt Cancer Center, Tampa, Florida 33612, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bromodomain-containing protein 2122Homo sapiensMutation(s): 0 
Gene Names: BRD2
UniProt & NIH Common Fund Data Resources
Find proteins for U3KQA6 (Homo sapiens)
Explore U3KQA6 
Go to UniProtKB:  U3KQA6
GTEx:  ENSG00000204256 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupU3KQA6
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
BMF BindingDB:  7LAH Kd: 50 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.206 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.181 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 55.87α = 90
b = 80.67β = 137.53
c = 47.68γ = 90
Software Package:
Software NamePurpose
XSCALEdata scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2021-08-11
    Type: Initial release
  • Version 1.1: 2021-11-17
    Changes: Database references
  • Version 1.2: 2021-11-24
    Changes: Database references
  • Version 1.3: 2023-10-18
    Changes: Data collection, Refinement description