5NNE

Crystal Structure of the first bromodomain of human BRD4 in complex with a diacetylated TOP2A peptide (K1201ac/K1204ac)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.15 Å
  • R-Value Free: 0.164 
  • R-Value Work: 0.139 
  • R-Value Observed: 0.140 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Interactome Rewiring Following Pharmacological Targeting of BET Bromodomains.

Lambert, J.P.Picaud, S.Fujisawa, T.Hou, H.Savitsky, P.Uuskula-Reimand, L.Gupta, G.D.Abdouni, H.Lin, Z.Y.Tucholska, M.Knight, J.D.R.Gonzalez-Badillo, B.St-Denis, N.Newman, J.A.Stucki, M.Pelletier, L.Bandeira, N.Wilson, M.D.Filippakopoulos, P.Gingras, A.C.

(2019) Mol Cell 73: 621-638.e17

  • DOI: https://doi.org/10.1016/j.molcel.2018.11.006
  • Primary Citation of Related Structures:  
    5NNC, 5NND, 5NNE, 5NNF, 5NNG, 6G0O, 6G0P, 6G0Q, 6G0R, 6G0S

  • PubMed Abstract: 

    Targeting bromodomains (BRDs) of the bromo-and-extra-terminal (BET) family offers opportunities for therapeutic intervention in cancer and other diseases. Here, we profile the interactomes of BRD2, BRD3, BRD4, and BRDT following treatment with the pan-BET BRD inhibitor JQ1, revealing broad rewiring of the interaction landscape, with three distinct classes of behavior for the 603 unique interactors identified. A group of proteins associate in a JQ1-sensitive manner with BET BRDs through canonical and new binding modes, while two classes of extra-terminal (ET)-domain binding motifs mediate acetylation-independent interactions. Last, we identify an unexpected increase in several interactions following JQ1 treatment that define negative functions for BRD3 in the regulation of rRNA synthesis and potentially RNAPII-dependent gene expression that result in decreased cell proliferation. Together, our data highlight the contributions of BET protein modules to their interactomes allowing for a better understanding of pharmacological rewiring in response to JQ1.


  • Organizational Affiliation

    Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.


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
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
GKA(ALY)GK(ALY)TQMYB [auth C]11Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for P11388 (Homo sapiens)
Explore P11388 
Go to UniProtKB:  P11388
PHAROS:  P11388
GTEx:  ENSG00000131747 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP11388
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
EDO
Query on EDO

Download Ideal Coordinates CCD File 
C [auth A]1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
ALY
Query on ALY
B [auth C]L-PEPTIDE LINKINGC8 H16 N2 O3LYS
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.15 Å
  • R-Value Free: 0.164 
  • R-Value Work: 0.139 
  • R-Value Observed: 0.140 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.347α = 90
b = 53.032β = 90
c = 58.193γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
SCALAdata scaling
PHASERphasing
Cootmodel building

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


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

Revision History  (Full details and data files)

  • Version 1.0: 2018-05-16
    Type: Initial release
  • Version 1.1: 2018-11-28
    Changes: Data collection, Database references
  • Version 1.2: 2018-12-26
    Changes: Data collection, Database references
  • Version 1.3: 2019-02-20
    Changes: Data collection, Database references
  • Version 1.4: 2024-01-17
    Changes: Data collection, Database references, Refinement description