7UUU | pdb_00007uuu

First bromodomain of BRDT liganded with compound 2c

  • Classification: TRANSCRIPTION
  • Organism(s): Homo sapiens
  • Expression System: Escherichia coli
  • Mutation(s): No 

  • Deposited: 2022-04-29 Released: 2022-08-24 
  • Deposition Author(s): Schonbrunn, E., Chan, A.
  • Funding Organization(s): National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.52 Å
  • R-Value Free: 
    0.179 (Depositor), 0.180 (DCC) 
  • R-Value Work: 
    0.153 (Depositor), 0.150 (DCC) 
  • R-Value Observed: 
    0.155 (Depositor) 

Starting Model: experimental
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Ligand Structure Quality Assessment 

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This is version 1.2 of the entry. See complete history


Literature

1,4-Dihydropyridinebutyrolactone-derived ring-opened ester and amide analogs targeting BET bromodomains.

Jiang, J.Zhao, P.L.Sigua, L.H.Chan, A.Schonbrunn, E.Qi, J.Georg, G.I.

(2022) Arch Pharm (Weinheim) 355: e2200288-e2200288

  • DOI: https://doi.org/10.1002/ardp.202200288
  • Primary Citation of Related Structures:  
    7UTY, 7UUU

  • PubMed Abstract: 

    Based on a previously reported 1,4-dihydropyridinebutyrolactone virtual screening hit, nine lactone ring-opened ester and seven amide analogs were prepared. The analogs were designed to provide interactions with residues at the entrance of the ZA loop of the testis-specific bromodomain (ZA) channel to enhance the affinity and selectivity for the bromodomain and extra-terminal (BET) subfamily of bromodomains. Compound testing by AlphaScreen showed that neither the affinity nor the selectivity of the ester and lactam analogs was improved for BRD4-1 and the first bromodomain of the testis-specific bromodomain (BRDT-1). The esters retained affinity comparable to the parent compound, whereas the affinity for the amide analogs was reduced 10-fold. A representative benzyl ester analog was found to retain high selectivity for BET bromodomains as shown by a BROMOscan. X-ray analysis of the allyl ester analog in complex with BRD4-1 and BRDT-1 revealed that the ester side chain is located next to the ZA loop and solvent exposed.


  • Organizational Affiliation

    Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bromodomain testis-specific protein113Homo sapiensMutation(s): 0 
Gene Names: BRDT
UniProt & NIH Common Fund Data Resources
Find proteins for Q58F21 (Homo sapiens)
Explore Q58F21 
Go to UniProtKB:  Q58F21
PHAROS:  Q58F21
GTEx:  ENSG00000137948 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ58F21
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.52 Å
  • R-Value Free:  0.179 (Depositor), 0.180 (DCC) 
  • R-Value Work:  0.153 (Depositor), 0.150 (DCC) 
  • R-Value Observed: 0.155 (Depositor) 
Space Group: P 42 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 50.81α = 90
b = 50.81β = 90
c = 99.09γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
XSCALEdata scaling
PHENIXphasing

Structure Validation

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Ligand Structure Quality Assessment 

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

Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)United States5P50HD093540

Revision History  (Full details and data files)

  • Version 1.0: 2022-08-24
    Type: Initial release
  • Version 1.1: 2022-11-09
    Changes: Database references
  • Version 1.2: 2023-10-18
    Changes: Data collection, Refinement description