5A85 | pdb_00005a85

N-TERMINAL BROMODOMAIN OF HUMAN BRD4 WITH 8-(3R,4R)-3-(cyclohexylmethoxy)piperidin-4-ylamino-3-methyl-1,2-dihydro-1,7- naphthyridin-2-one

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.72 Å
  • R-Value Free: 
    0.236 (Depositor), 0.240 (DCC) 
  • R-Value Work: 
    0.185 (Depositor), 0.200 (DCC) 
  • R-Value Observed: 
    0.188 (Depositor) 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted 78JClick on this verticalbar to view details

This is version 1.2 of the entry. See complete history. 


Literature

Structure-Based Optimization of Naphthyridones Into Potent Atad2 Bromodomain Inhibitors.

Bamborough, P., Chung, C., Furze, R.C., Grandi, P., Michon, A., Sheppard, R.J., Barnett, H., Diallo, H., Dixon, D.P., Douault, C., Jones, E.J., Karamshi, B., Mitchell, D.J., Prinjha, R.K., Rau, C., Watson, R.J., Werner, T., Demont, E.H.

(2015) J Med Chem 58: 6151

  • DOI: https://doi.org/10.1021/acs.jmedchem.5b00773
  • Primary Citation of Related Structures:  
    5A81, 5A82, 5A83, 5A85

  • PubMed Abstract: 

    ATAD2 is a bromodomain-containing protein whose overexpression is linked to poor outcomes in a number of different cancer types. To date, no potent and selective inhibitors of the bromodomain have been reported. This article describes the structure-based optimization of a series of naphthyridones from micromolar leads with no selectivity over the BET bromodomains to inhibitors with sub-100 nM ATAD2 potency and 100-fold BET selectivity.

    • Organizational Affiliation: 

    ∥Cellzome GmbH, Molecular Discovery Research, 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 
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
78J
Query on 78J
Download Ideal Coordinates CCD File 
C [auth A](3R,4R)-3-(cyclohexylmethoxy)piperidin-4-yl]amino}-3-methyl-1,2-dihydro-1,7-naphthyridin-2-one
C21 H30 N4 O2
DQJOFVKRLCBKNO-QZTJIDSGSA-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
78J BindingDB:  5A85 IC50: min: 3981, max: 5012 (nM) from 3 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.72 Å
  • R-Value Free:  0.236 (Depositor), 0.240 (DCC) 
  • R-Value Work:  0.185 (Depositor), 0.200 (DCC) 
  • R-Value Observed: 0.188 (Depositor) 
Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 43.189α = 90
b = 48.652β = 90
c = 61.052γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted 78JClick on this verticalbar to view details

View more in-depth experimental data
Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-08-12
    Type: Initial release
  • Version 1.1: 2015-08-26
    Changes: Database references
  • Version 1.2: 2024-05-08
    Changes: Data collection, Database references, Derived calculations, Other