5LUU

Structure of the first bromodomain of BRD4 with a pyrazolo[4,3-c]pyridin fragment


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.61 Å
  • R-Value Free: 0.206 
  • R-Value Work: 0.169 
  • R-Value Observed: 0.171 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of New Bromodomain Scaffolds by Biosensor Fragment Screening.

Navratilova, I.Aristotelous, T.Picaud, S.Chaikuad, A.Knapp, S.Filappakopoulos, P.Hopkins, A.L.

(2016) ACS Med Chem Lett 7: 1213-1218

  • DOI: https://doi.org/10.1021/acsmedchemlett.6b00154
  • Primary Citation of Related Structures:  
    5LUU, 5LVQ, 5LVR, 5TB6

  • PubMed Abstract: 

    The discovery of novel bromodomain inhibitors by fragment screening is complicated by the presence of dimethyl sulfoxide (DMSO), an acetyl-lysine mimetic, that can compromise the detection of low affinity fragments. We demonstrate surface plasmon resonance as a primary fragment screening approach for the discovery of novel bromodomain scaffolds, by describing a protocol to overcome the DMSO interference issue. We describe the discovery of several novel small molecules scaffolds that inhibit the bromodomains PCAF, BRD4, and CREBBP, representing canonical members of three out of the seven subfamilies of bromodomains. High-resolution crystal structures of the complexes of key fragments binding to BRD4(1), CREBBP, and PCAF were determined to provide binding mode data to aid the development of potent and selective inhibitors of PCAF, CREBBP, and BRD4.


  • Organizational Affiliation

    Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dow Street, Dundee DD1 5EH, United Kingdom.


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
Binding Affinity Annotations 
IDSourceBinding Affinity
77X Binding MOAD:  5LUU Kd: 8630 (nM) from 1 assay(s)
BindingDB:  5LUU Kd: min: 8630, max: 9.70e+4 (nM) from 4 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.61 Å
  • R-Value Free: 0.206 
  • R-Value Work: 0.169 
  • R-Value Observed: 0.171 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 37.75α = 90
b = 44.21β = 90
c = 78.27γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction
MOSFLMdata reduction
CrystalCleardata collection

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Wellcome TrustUnited Kingdom095751/Z/11/Z
Wellcome TrustUnited Kingdom092809/Z/10/Z

Revision History  (Full details and data files)

  • Version 1.0: 2016-10-12
    Type: Initial release
  • Version 1.1: 2017-01-11
    Changes: Database references
  • Version 1.2: 2017-11-08
    Changes: Source and taxonomy