5DLX

FIRST DOMAIN OF HUMAN BROMODOMAIN BRD4 IN COMPLEX WITH INHIBITOR N-{3-[4-(3-chlorophenyl)piperazin-1-yl]propyl}-1-{3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl}piperidine-4-carboxamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.207 
  • R-Value Work: 0.125 
  • R-Value Observed: 0.130 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Protein-Protein Interaction Inhibition (2P2I)-Oriented Chemical Library Accelerates Hit Discovery.

Milhas, S.Raux, B.Betzi, S.Derviaux, C.Roche, P.Restouin, A.Basse, M.J.Rebuffet, E.Lugari, A.Badol, M.Kashyap, R.Lissitzky, J.C.Eydoux, C.Hamon, V.Gourdel, M.E.Combes, S.Zimmermann, P.Aurrand-Lions, M.Roux, T.Rogers, C.Muller, S.Knapp, S.Trinquet, E.Collette, Y.Guillemot, J.C.Morelli, X.

(2016) ACS Chem Biol 11: 2140-2148

  • DOI: https://doi.org/10.1021/acschembio.6b00286
  • Primary Citation of Related Structures:  
    5DLX, 5DLZ

  • PubMed Abstract: 

    Protein-protein interactions (PPIs) represent an enormous source of opportunity for therapeutic intervention. We and others have recently pinpointed key rules that will help in identifying the next generation of innovative drugs to tackle this challenging class of targets within the next decade. We used these rules to design an oriented chemical library corresponding to a set of diverse "PPI-like" modulators with cores identified as privileged structures in therapeutics. In this work, we purchased the resulting 1664 structurally diverse compounds and evaluated them on a series of representative protein-protein interfaces with distinct "druggability" potential using homogeneous time-resolved fluorescence (HTRF) technology. For certain PPI classes, analysis of the hit rates revealed up to 100 enrichment factors compared with nonoriented chemical libraries. This observation correlates with the predicted "druggability" of the targets. A specific focus on selectivity profiles, the three-dimensional (3D) molecular modes of action resolved by X-ray crystallography, and the biological activities of identified hits targeting the well-defined "druggable" bromodomains of the bromo and extraterminal (BET) family are presented as a proof-of-concept. Overall, our present study illustrates the potency of machine learning-based oriented chemical libraries to accelerate the identification of hits targeting PPIs. A generalization of this method to a larger set of compounds will accelerate the discovery of original and potent probes for this challenging class of targets.


  • Organizational Affiliation

    CNRS, INSERM, Aix-Marseille Université, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille , CS30059, 13273 Marseille Cedex 9, 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
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
5D2
Query on 5D2

Download Ideal Coordinates CCD File 
B [auth A]N-{3-[4-(3-chlorophenyl)piperazin-1-yl]propyl}-1-(3-methyl[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidine-4-carboxamide
C25 H33 Cl N8 O
JKOZTTFNOFUTMV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
5D2 Binding MOAD:  5DLX Kd: 2000 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.207 
  • R-Value Work: 0.125 
  • R-Value Observed: 0.130 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.723α = 90
b = 48.509β = 90
c = 58.094γ = 90
Software Package:
Software NamePurpose
XDSdata reduction
XDSdata scaling
PHASERphasing
REFMACrefinement

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-06-01
    Type: Initial release
  • Version 1.1: 2016-08-31
    Changes: Database references
  • Version 1.2: 2024-01-10
    Changes: Data collection, Database references, Refinement description