6FNX

FIRST DOMAIN OF HUMAN BROMODOMAIN BRD4 IN COMPLEX WITH INHIBITOR F1

  • Classification: DNA BINDING PROTEIN
  • Organism(s): Homo sapiens
  • Expression System: Escherichia coli BL21
  • Mutation(s): No 

  • Deposited: 2018-02-05 Released: 2018-06-20 
  • Deposition Author(s): Raux, B., Betzi, S.
  • Funding Organization(s): Canceropole PACA Institut National du Cancer Conseil Regional PACA, Fondation FRM pour la Recherche Medicale, Agence Nationale de la Recherche (ANR), Integrated Structural Biology (FRISBI)

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.19 Å
  • R-Value Free: 0.276 
  • R-Value Work: 0.232 
  • R-Value Observed: 0.234 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Integrated Strategy for Lead Optimization Based on Fragment Growing: The Diversity-Oriented-Target-Focused-Synthesis Approach.

Hoffer, L.Voitovich, Y.V.Raux, B.Carrasco, K.Muller, C.Fedorov, A.Y.Derviaux, C.Amouric, A.Betzi, S.Horvath, D.Varnek, A.Collette, Y.Combes, S.Roche, P.Morelli, X.

(2018) J Med Chem 61: 5719-5732

  • DOI: https://doi.org/10.1021/acs.jmedchem.8b00653
  • Primary Citation of Related Structures:  
    6FNX, 6FO5

  • PubMed Abstract: 

    Over the past few decades, hit identification has been greatly facilitated by advances in high-throughput and fragment-based screenings. One major hurdle remaining in drug discovery is process automation of hit-to-lead (H2L) optimization. Here, we report a time- and cost-efficient integrated strategy for H2L optimization as well as a partially automated design of potent chemical probes consisting of a focused-chemical-library design and virtual screening coupled with robotic diversity-oriented de novo synthesis and automated in vitro evaluation. The virtual library is generated by combining an activated fragment, corresponding to the substructure binding to the target, with a collection of functionalized building blocks using in silico encoded chemical reactions carefully chosen from a list of one-step organic transformations relevant in medicinal chemistry. The proof of concept was demonstrated using the optimization of bromodomain inhibitors as a test case, leading to the validation of several compounds with improved affinity by several orders of magnitude.


  • Organizational Affiliation

    CRCM, CNRS, Inserm, Institut Paoli-Calmettes , Aix-Marseille University , 13009 Marseille , France.


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
DYZ Binding MOAD:  6FNX IC50: 1.26e+4 (nM) from 1 assay(s)
BindingDB:  6FNX IC50: 1.26e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.19 Å
  • R-Value Free: 0.276 
  • R-Value Work: 0.232 
  • R-Value Observed: 0.234 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 37.863α = 90
b = 44.175β = 90
c = 78.156γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
XDSdata scaling
Cootmodel building
PHASERphasing

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Canceropole PACA Institut National du Cancer Conseil Regional PACAFrance--
Fondation FRM pour la Recherche MedicaleFrance--
Agence Nationale de la Recherche (ANR)FranceANR-15-CE18-0023
Integrated Structural Biology (FRISBI)FranceANR-10-INSB-05-01

Revision History  (Full details and data files)

  • Version 1.0: 2018-06-20
    Type: Initial release
  • Version 1.1: 2018-07-04
    Changes: Data collection, Database references
  • Version 1.2: 2018-07-25
    Changes: Data collection, Database references
  • Version 1.3: 2024-01-17
    Changes: Author supporting evidence, Data collection, Database references, Refinement description