6CJ1

Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor JWG071

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

  • Deposited: 2018-02-25 Released: 2018-08-29 
  • 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: 1.53 Å
  • R-Value Free: 0.192 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.175 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 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
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FND
Query on FND

Download Ideal Coordinates CCD File 
C [auth A]11-[(2S)-butan-2-yl]-2-({2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]phenyl}amino)-5-methyl-5,11-dihydro-6H-pyrimido[4,5-b][1,4]benzodiazepin-6-one
C34 H44 N8 O3
ACWOMSOYIIVIRV-QHCPKHFHSA-N
F2S (Subject of Investigation/LOI)
Query on F2S

Download Ideal Coordinates CCD File 
B [auth A]11-[(2R)-butan-2-yl]-2-({2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]phenyl}amino)-5-methyl-5,11-dihydro-6H-pyrimido[4,5-b][1,4]benzodiazepin-6-one
C34 H44 N8 O3
ACWOMSOYIIVIRV-HSZRJFAPSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
D [auth A],
E [auth A],
F [auth A]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
NO3
Query on NO3

Download Ideal Coordinates CCD File 
G [auth A],
H [auth A]
NITRATE ION
N O3
NHNBFGGVMKEFGY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
FND Binding MOAD:  6CJ1 IC50: 6310 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.53 Å
  • R-Value Free: 0.192 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.175 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 40.05α = 90
b = 42.227β = 90
c = 84.9γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing

Structure Validation

View Full Validation Report



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: 2018-08-29
    Type: Initial release
  • Version 1.1: 2018-10-03
    Changes: Data collection, Database references
  • Version 1.2: 2019-02-20
    Changes: Author supporting evidence, Data collection
  • Version 1.3: 2020-01-01
    Changes: Author supporting evidence
  • Version 1.4: 2023-10-04
    Changes: Data collection, Database references, Refinement description