6PSB

Crystal structure of BRD4 bromodomain 1 with N-methylpyrrolidin-2-one (NMP) derivative 18 (5-{[(3R)-1-methyl-5-oxopyrrolidin-3-yl]methyl}-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.59 Å
  • R-Value Free: 0.209 
  • R-Value Work: 0.170 
  • R-Value Observed: 0.172 

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This is version 1.2 of the entry. See complete history


Literature

Synthesis and elaboration of N-methylpyrrolidone as an acetamide fragment substitute in bromodomain inhibition.

Hilton-Proctor, J.P.Ilyichova, O.Zheng, Z.Jennings, I.G.Johnstone, R.W.Shortt, J.Mountford, S.J.Scanlon, M.J.Thompson, P.E.

(2019) Bioorg Med Chem 27: 115157-115157

  • DOI: https://doi.org/10.1016/j.bmc.2019.115157
  • Primary Citation of Related Structures:  
    6PRT, 6PS9, 6PSB

  • PubMed Abstract: 

    N-Methylpyrrolidone is a solvent molecule which has been shown to compete with acetyl-lysine-containing peptides for binding to bromodomains. From crystallographic studies, it has also been shown to closely mimic the acetamide binding motif in several bromodomains, but has not yet been directly pursued as a fragment in bromodomain inhibition. In this paper, we report the elaboration of N-methylpyrrolidone as a potential lead in fragment-based drug design. Firstly, N-methylpyrrolidone was functionalised to provide points for chemical elaboration. Then, the moiety was incorporated into analogues of the reported bromodomain inhibitor, Olinone. X-ray crystallography revealed that the modified analogues showed comparable binding affinity and structural mimicry to Olinone in the bromodomain binding site.


  • Organizational Affiliation

    Medicinal Chemistry, Monash Institute of Pharmaceutical Science, Monash University, 381 Royal Parade, Parkville, Victoria, Australia.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bromodomain-containing protein 4126Homo 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
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
Y18 (Subject of Investigation/LOI)
Query on Y18

Download Ideal Coordinates CCD File 
B [auth A]5-{[(3R)-1-methyl-5-oxopyrrolidin-3-yl]methyl}-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one
C17 H19 N3 O2
UERBETVZEWZRSL-NSHDSACASA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
Y18 Binding MOAD:  6PSB IC50: 2.40e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.59 Å
  • R-Value Free: 0.209 
  • R-Value Work: 0.170 
  • R-Value Observed: 0.172 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.614α = 90
b = 52.008β = 90
c = 58γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-11-27
    Type: Initial release
  • Version 1.1: 2019-12-04
    Changes: Database references
  • Version 1.2: 2023-10-11
    Changes: Data collection, Database references, Refinement description