6CJ2

Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor JWG056

  • Classification: TRANSCRIPTION/INHIBITOR
  • Organism(s): Homo sapiens
  • Expression System: Escherichia coli
  • Mutation(s): No 

  • Deposited: 2018-02-26 Released: 2019-03-06 
  • Deposition Author(s): Xu, X., Blacklow, S.C.
  • Funding Organization(s): National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS), Leukemia & Lymphoma Society

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.47 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.183 
  • R-Value Observed: 0.184 

Starting Model: experimental
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This is version 1.3 of the entry. See complete history


Literature

Structural and Atropisomeric Factors Governing the Selectivity of Pyrimido-benzodiazipinones as Inhibitors of Kinases and Bromodomains.

Wang, J.Erazo, T.Ferguson, F.M.Buckley, D.L.Gomez, N.Munoz-Guardiola, P.Dieguez-Martinez, N.Deng, X.Hao, M.Massefski, W.Fedorov, O.Offei-Addo, N.K.Park, P.M.Dai, L.DiBona, A.Becht, K.Kim, N.D.McKeown, M.R.Roberts, J.M.Zhang, J.Sim, T.Alessi, D.R.Bradner, J.E.Lizcano, J.M.Blacklow, S.C.Qi, J.Xu, X.Gray, N.S.

(2018) ACS Chem Biol 13: 2438-2448

  • DOI: https://doi.org/10.1021/acschembio.7b00638
  • Primary Citation of Related Structures:  
    5WA5, 6CD4, 6CD5, 6CIS, 6CIY, 6CJ1, 6CJ2

  • PubMed Abstract: 

    Bromodomains have been pursued intensively over the past several years as emerging targets for the development of anticancer and anti-inflammatory agents. It has recently been shown that some kinase inhibitors are able to potently inhibit the bromodomains of BRD4. The clinical activities of PLK inhibitor BI-2536 and JAK2-FLT3 inhibitor TG101348 have been attributed to this unexpected polypharmacology, indicating that dual-kinase/bromodomain activity may be advantageous in a therapeutic context. However, for target validation and biological investigation, a more selective target profile is desired. Here, we report that benzo[e]pyrimido-[5,4- b]diazepine-6(11H)-ones, versatile ATP-site directed kinase pharmacophores utilized in the development of inhibitors of multiple kinases, including several previously reported kinase chemical probes, are also capable of exhibiting potent BRD4-dependent pharmacology. Using a dual kinase-bromodomain inhibitor of the kinase domains of ERK5 and LRRK2, and the bromodomain of BRD4 as a case study, we define the structure-activity relationships required to achieve dual kinase/BRD4 activity, as well as how to direct selectivity toward inhibition of either ERK5 or BRD4. This effort resulted in identification of one of the first reported kinase-selective chemical probes for ERK5 (JWG-071), a BET selective inhibitor with 1 μM BRD4 IC 50 (JWG-115), and additional inhibitors with rationally designed polypharmacology (JWG-047, JWG-069). Co-crystallography of seven representative inhibitors with the first bromodomain of BRD4 demonstrate that distinct atropisomeric conformers recognize the kinase ATP-site and the BRD4 acetyl lysine binding site, conformational preferences supported by rigid docking studies.


  • Organizational Affiliation

    Department of Cancer Biology , Dana-Farber Cancer Institute , Boston , Massachusetts 02215 , United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bromodomain-containing protein 4125Homo 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
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
X27 (Subject of Investigation/LOI)
Query on X27

Download Ideal Coordinates CCD File 
B [auth A]2-{[3-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-5-methyl-11-(propan-2-yl)-5,11-dihydro-6H-pyrimido[4,5-b][1,4]benzodiazepin-6-one
C27 H33 N7 O2
OIBWIGLECGTHPO-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.47 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.183 
  • R-Value Observed: 0.184 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 32.816α = 90
b = 47.412β = 90
c = 78.666γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesP50 GM107618
Leukemia & Lymphoma SocietyUnited StatesSCOR 7003-13

Revision History  (Full details and data files)

  • Version 1.0: 2019-03-06
    Type: Initial release
  • Version 1.1: 2020-01-01
    Changes: Author supporting evidence
  • Version 1.2: 2020-09-16
    Changes: Database references
  • Version 1.3: 2023-10-04
    Changes: Data collection, Database references, Refinement description