4FLP

Crystal Structure of the first bromodomain of human BRDT in complex with the inhibitor JQ1


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.23 Å
  • R-Value Free: 0.255 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.213 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Small-Molecule Inhibition of BRDT for Male Contraception.

Matzuk, M.M.McKeown, M.R.Filippakopoulos, P.Li, Q.Ma, L.Agno, J.E.Lemieux, M.E.Picaud, S.Yu, R.N.Qi, J.Knapp, S.Bradner, J.E.

(2012) Cell 150: 673-684

  • DOI: https://doi.org/10.1016/j.cell.2012.06.045
  • Primary Citation of Related Structures:  
    4FLP

  • PubMed Abstract: 

    A pharmacologic approach to male contraception remains a longstanding challenge in medicine. Toward this objective, we explored the spermatogenic effects of a selective small-molecule inhibitor (JQ1) of the bromodomain and extraterminal (BET) subfamily of epigenetic reader proteins. Here, we report potent inhibition of the testis-specific member BRDT, which is essential for chromatin remodeling during spermatogenesis. Biochemical and crystallographic studies confirm that occupancy of the BRDT acetyl-lysine binding pocket by JQ1 prevents recognition of acetylated histone H4. Treatment of mice with JQ1 reduced seminiferous tubule area, testis size, and spermatozoa number and motility without affecting hormone levels. Although JQ1-treated males mate normally, inhibitory effects of JQ1 evident at the spermatocyte and round spermatid stages cause a complete and reversible contraceptive effect. These data establish a new contraceptive that can cross the blood:testis boundary and inhibit bromodomain activity during spermatogenesis, providing a lead compound targeting the male germ cell for contraception.


  • Organizational Affiliation

    Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA. mmatzuk@bcm.edu


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bromodomain testis-specific protein
A, B
119Homo 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
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
JQ1
Query on JQ1

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
(6S)-6-(2-tert-butoxy-2-oxoethyl)-4-(4-chlorophenyl)-2,3,9-trimethyl-6,7-dihydrothieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-10-ium
C23 H26 Cl N4 O2 S
DNVXATUJJDPFDM-KRWDZBQOSA-O
K
Query on K

Download Ideal Coordinates CCD File 
E [auth B]POTASSIUM ION
K
NPYPAHLBTDXSSS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
JQ1 Binding MOAD:  4FLP Kd: 190.1 (nM) from 1 assay(s)
PDBBind:  4FLP Kd: 190.1 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.23 Å
  • R-Value Free: 0.255 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.213 
  • Space Group: P 21 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 37.4α = 90
b = 57.42β = 90
c = 128.69γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction
DNAdata collection
MOSFLMdata reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2012-07-11
    Type: Initial release
  • Version 1.1: 2012-08-29
    Changes: Database references
  • Version 1.2: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description