6HDQ

N-TERMINAL BROMODOMAIN OF HUMAN BRD4 WITH : 8-(((1R,2R,3R,5S)-2-(2-(4,4-difluorocyclohexyl)ethyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-3-methyl-5-(5-methylpyridin-3-yl)-1,7-naphthyridin-2(1H)-one

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.241 
  • R-Value Work: 0.205 
  • R-Value Observed: 0.206 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history. 


Literature

Aiming to Miss a Moving Target: Bromo and Extra Terminal Domain (BET) Selectivity in Constrained ATAD2 Inhibitors.

Bamborough, P., Chung, C.W., Furze, R.C., Grandi, P., Michon, A.M., Watson, R.J., Mitchell, D.J., Barnett, H., Prinjha, R.K., Rau, C., Sheppard, R.J., Werner, T., Demont, E.H.

(2018) J Med Chem 61: 8321-8336

  • DOI: https://doi.org/10.1021/acs.jmedchem.8b00862
  • Primary Citation of Related Structures:  
    6HDN, 6HDO, 6HDQ

  • PubMed Abstract: 

    ATAD2 is a cancer-associated protein whose bromodomain has been described as among the least druggable of its class. In our recent disclosure of the first chemical probe against this bromodomain, GSK8814 (6), we described the use of a conformationally constrained methoxy piperidine to gain selectivity over the BET bromodomains. Here we describe an orthogonal conformational restriction strategy of the piperidine ring to give potent and selective tropane inhibitors and show structural insights into why this was more challenging than expected. Greater understanding of why different rational approaches succeeded or failed should help in the future design of selectivity in the bromodomain family.

    • Organizational Affiliation: 

    Molecular Discovery Research, Cellzome GmbH , GlaxoSmithKline , Meyerhofstrasse 1 , 69117 Heidelberg , Germany.


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: BRD4, HUNK1
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 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FZE
Query on FZE
Download Ideal Coordinates CCD File 
C [auth A]8-(((1R,2R,3R,5S)-2-(2-(4,4-difluorocyclohexyl)ethyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-3-methyl-5-(5-methylpyridin-3-yl)-1,7-naphthyridin-2(1H)-one
C30 H37 F2 N5 O
XSDXNVMLXLEGSP-ULDOEVFSSA-N
EDO
Query on EDO
Download Ideal Coordinates CCD File 
B [auth A]1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
FZE Binding MOAD:  6HDQ IC50: 5010 (nM) from 1 assay(s)
BindingDB:  6HDQ IC50: 5012 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.241 
  • R-Value Work: 0.205 
  • R-Value Observed: 0.206 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 40.36α = 90
b = 112.7β = 90
c = 30.42γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
SCALAdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

  • Released Date: 2018-09-26 
    • Deposition Author(s): Chung, C.

Revision History  (Full details and data files)

  • Version 1.0: 2018-09-26
    Type: Initial release
  • Version 1.1: 2018-10-10
    Changes: Data collection, Database references