5HRW

Crystal structure of the fifth bromodomain of human PB1 in complex with 1-propylisochromeno[3,4-c]pyrazol-5(2H)-one) compound


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.202 
  • R-Value Observed: 0.204 

Starting Model: experimental
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This is version 1.2 of the entry. See complete history


Literature

Discovery and Optimization of a Selective Ligand for the Switch/Sucrose Nonfermenting-Related Bromodomains of Polybromo Protein-1 by the Use of Virtual Screening and Hydration Analysis.

Myrianthopoulos, V.Gaboriaud-Kolar, N.Tallant, C.Hall, M.L.Grigoriou, S.Brownlee, P.M.Fedorov, O.Rogers, C.Heidenreich, D.Wanior, M.Drosos, N.Mexia, N.Savitsky, P.Bagratuni, T.Kastritis, E.Terpos, E.Filippakopoulos, P.Muller, S.Skaltsounis, A.L.Downs, J.A.Knapp, S.Mikros, E.

(2016) J Med Chem 59: 8787-8803

  • DOI: https://doi.org/10.1021/acs.jmedchem.6b00355
  • Primary Citation of Related Structures:  
    5HRV, 5HRW, 5HRX, 5II1, 5II2, 5IID

  • PubMed Abstract: 

    Bromodomains (BRDs) are epigenetic interaction domains currently recognized as emerging drug targets for development of anticancer or anti-inflammatory agents. In this study, development of a selective ligand of the fifth BRD of polybromo protein-1 (PB1(5)) related to switch/sucrose nonfermenting (SWI/SNF) chromatin remodeling complexes is presented. A compound collection was evaluated by consensus virtual screening and a hit was identified. The biophysical study of protein-ligand interactions was performed using X-ray crystallography and isothermal titration calorimetry. Collective data supported the hypothesis that affinity improvement could be achieved by enhancing interactions of the complex with the solvent. The derived SAR along with free energy calculations and a consensus hydration analysis using WaterMap and SZmap algorithms guided rational design of a set of novel analogues. The most potent analogue demonstrated high affinity of 3.3 μM and an excellent selectivity profile, thus comprising a promising lead for the development of chemical probes targeting PB1(5).


  • Organizational Affiliation

    Department of Pharmacy, University of Athens , Panepistimiopolis Zografou, GR-15771 Athens, Greece.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Protein polybromo-1
A, B
124Homo sapiensMutation(s): 0 
Gene Names: PBRM1BAF180PB1
UniProt & NIH Common Fund Data Resources
Find proteins for Q86U86 (Homo sapiens)
Explore Q86U86 
Go to UniProtKB:  Q86U86
PHAROS:  Q86U86
GTEx:  ENSG00000163939 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ86U86
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
64E
Query on 64E

Download Ideal Coordinates CCD File 
C [auth A],
I [auth B]
1-propylisochromeno[3,4-c]pyrazol-5(3H)-one
C13 H12 N2 O2
URRDWILHXUGXPV-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
H [auth A]SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
EDO
Query on EDO

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

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.202 
  • R-Value Observed: 0.204 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.111α = 90
b = 59.101β = 90
c = 105.485γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2016-10-12
    Type: Initial release
  • Version 1.1: 2016-10-26
    Changes: Database references
  • Version 1.2: 2024-01-10
    Changes: Data collection, Database references, Refinement description