5LJ1

N-TERMINAL BROMODOMAIN OF HUMAN BRD4 WITH 8-(((3R,4R,5S)-3-((4,4-difluorocyclohexyl)methoxy)-5-methoxypiperidin-4-yl)amino)-3-methyl-5-(5-methylpyridin-3-yl)-1,7-naphthyridin-2(1H)-one


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.237 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.171 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

A Chemical Probe for the ATAD2 Bromodomain.

Bamborough, P.Chung, C.W.Demont, E.H.Furze, R.C.Bannister, A.J.Che, K.H.Diallo, H.Douault, C.Grandi, P.Kouzarides, T.Michon, A.M.Mitchell, D.J.Prinjha, R.K.Rau, C.Robson, S.Sheppard, R.J.Upton, R.Watson, R.J.

(2016) Angew Chem Int Ed Engl 55: 11382-11386

  • DOI: https://doi.org/10.1002/anie.201603928
  • Primary Citation of Related Structures:  
    5LJ0, 5LJ1, 5LJ2

  • PubMed Abstract: 

    ATAD2 is a cancer-associated protein whose bromodomain has been described as among the least druggable of that target class. Starting from a potent lead, permeability and selectivity were improved through a dual approach: 1) using CF2 as a sulfone bio-isostere to exploit the unique properties of fluorine, and 2) using 1,3-interactions to control the conformation of a piperidine ring. This resulted in the first reported low-nanomolar, selective and cell permeable chemical probe for ATAD2.


  • Organizational Affiliation

    GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK. Paul.A.Bamborough@gsk.com.


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: 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 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
6XX
Query on 6XX

Download Ideal Coordinates CCD File 
C [auth A]8-(((3R,4R,5S)-3-((4,4-difluorocyclohexyl)methoxy)-5-methoxypiperidin-4-yl)amino)-3-methyl-5-(5-methylpyridin-3-yl)-1,7-naphthyridin-2(1H)-one
C28 H35 F2 N5 O3
YDPMMWAOCCOULO-JBRSBNLGSA-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
6XX BindingDB:  5LJ1 IC50: min: 2.51e+4, max: 3.16e+4 (nM) from 2 assay(s)
Binding MOAD:  5LJ1 IC50: 3.16e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.237 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.171 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.67α = 90
b = 109.19β = 90
c = 30.26γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-08-31
    Type: Initial release
  • Version 1.1: 2016-09-14
    Changes: Database references