5T4V

Crystal structure of the bromodomain of human BRPF1 in complex with NI-48 ligand


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.65 Å
  • R-Value Free: 0.250 
  • R-Value Work: 0.210 
  • R-Value Observed: 0.212 

Starting Model: experimental
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This is version 1.1 of the entry. See complete history


Literature

Design of a Biased Potent Small Molecule Inhibitor of the Bromodomain and PHD Finger-Containing (BRPF) Proteins Suitable for Cellular and in Vivo Studies.

Igoe, N.Bayle, E.D.Fedorov, O.Tallant, C.Savitsky, P.Rogers, C.Owen, D.R.Deb, G.Somervaille, T.C.Andrews, D.M.Jones, N.Cheasty, A.Ryder, H.Brennan, P.E.Muller, S.Knapp, S.Fish, P.V.

(2017) J Med Chem 60: 668-680

  • DOI: https://doi.org/10.1021/acs.jmedchem.6b01583
  • Primary Citation of Related Structures:  
    5T4U, 5T4V

  • PubMed Abstract: 

    The BRPF (bromodomain and PHD finger-containing) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Evaluation of the BRPF family as a potential drug target is at an early stage although there is an emerging understanding of a role in acute myeloid leukemia (AML). We report the optimization of fragment hit 5b to 13-d as a biased, potent inhibitor of the BRD of the BRPFs with excellent selectivity over nonclass IV BRD proteins. Evaluation of 13-d in a panel of cancer cell lines showed a selective inhibition of proliferation of a subset of AML lines. Pharmacokinetic studies established that 13-d had properties compatible with oral dosing in mouse models of disease (F po 49%). We propose that NI-42 (13-d) is a new chemical probe for the BRPFs suitable for cellular and in vivo studies to explore the fundamental biology of these proteins.


  • Organizational Affiliation

    UCL School of Pharmacy, University College London , 29/39 Brunswick Square, London WC1N 1AX, U.K.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Peregrin116Homo sapiensMutation(s): 0 
Gene Names: BRPF1BR140
UniProt & NIH Common Fund Data Resources
Find proteins for P55201 (Homo sapiens)
Explore P55201 
Go to UniProtKB:  P55201
PHAROS:  P55201
GTEx:  ENSG00000156983 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP55201
Sequence Annotations
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  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
N48 BindingDB:  5T4V IC50: 60 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.65 Å
  • R-Value Free: 0.250 
  • R-Value Work: 0.210 
  • R-Value Observed: 0.212 
  • Space Group: I 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 47.086α = 90
b = 60.145β = 99.83
c = 51.948γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2017-02-08
    Type: Initial release
  • Version 1.1: 2024-01-17
    Changes: Data collection, Database references, Refinement description