4A9O

N-TERMINAL BROMODOMAIN OF HUMAN BRD2 WITH 5 ethyl-3-methyl-4-phenyl-1, 2-oxazole


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.78 Å
  • R-Value Free: 0.198 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.173 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.0 of the entry. See complete history


Literature

Fragment-Based Discovery of Bromodomain Inhibitors Part 2: Optimization of Phenylisoxazole Sulfonamides.

Bamborough, P.Diallo, H.Goodacre, J.D.Gordon, L.Lewis, A.Seal, J.T.Wilson, D.M.Woodrow, M.D.Chung, C.W.

(2012) J Med Chem 55: 587

  • DOI: https://doi.org/10.1021/jm201283q
  • Primary Citation of Related Structures:  
    4A9M, 4A9N, 4A9O, 4ALH

  • PubMed Abstract: 

    Bromodomains are epigenetic reader modules that regulate gene transcription through their recognition of acetyl-lysine modified histone tails. Inhibitors of this protein-protein interaction have the potential to modulate multiple diseases as demonstrated by the profound anti-inflammatory and antiproliferative effects of a recently disclosed class of BET compounds. While these compounds were discovered using phenotypic assays, here we present a highly efficient alternative approach to find new chemical templates, exploiting the abundant structural knowledge that exists for this target class. A phenyl dimethyl isoxazole chemotype resulting from a focused fragment screen has been rapidly optimized through structure-based design, leading to a sulfonamide series showing anti-inflammatory activity in cellular assays. This proof-of-principle experiment demonstrates the tractability of the BET family and bromodomain target class to fragment-based hit discovery and structure-based lead optimization.


  • Organizational Affiliation

    Epinova DPU, Immuno-Inflammation Centre of Excellence for Drug Discovery, GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire 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 2
A, B, C
154Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for P25440 (Homo sapiens)
Explore P25440 
Go to UniProtKB:  P25440
PHAROS:  P25440
GTEx:  ENSG00000204256 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP25440
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
A9O
Query on A9O

Download Ideal Coordinates CCD File 
E [auth A],
I [auth B],
J [auth C]
5-ETHYL-3-METHYL-4-PHENYL-1,2-OXAZOLE
C12 H13 N O
RWCFZRPXMBQSOA-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
F [auth A],
G [auth A],
K [auth C]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
EDO
Query on EDO

Download Ideal Coordinates CCD File 
D [auth A],
H [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.78 Å
  • R-Value Free: 0.198 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.173 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 113.628α = 90
b = 55.692β = 94
c = 68.077γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data reduction
SCALEPACKdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-02-08
    Type: Initial release