4Z6I

Crystal structure of BRD9 bromodomain in complex with a substituted valerolactam quinolone ligand


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.184 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

LP99: Discovery and Synthesis of the First Selective BRD7/9 Bromodomain Inhibitor.

Clark, P.G.Vieira, L.C.Tallant, C.Fedorov, O.Singleton, D.C.Rogers, C.M.Monteiro, O.P.Bennett, J.M.Baronio, R.Muller, S.Daniels, D.L.Mendez, J.Knapp, S.Brennan, P.E.Dixon, D.J.

(2015) Angew Chem Int Ed Engl 54: 6217-6221

  • DOI: https://doi.org/10.1002/anie.201501394
  • Primary Citation of Related Structures:  
    4Z6H, 4Z6I

  • PubMed Abstract: 

    The bromodomain-containing proteins BRD9 and BRD7 are part of the human SWI/SNF chromatin-remodeling complexes BAF and PBAF. To date, no selective inhibitor for BRD7/9 has been reported despite its potential value as a biological tool or as a lead for future therapeutics. The quinolone-fused lactam LP99 is now reported as the first potent and selective inhibitor of the BRD7 and BRD9 bromodomains. Development of LP99 from a fragment hit was expedited through balancing structure-based inhibitor design and biophysical characterization against tractable chemical synthesis: Complexity-building nitro-Mannich/lactamization cascade processes allowed for early structure-activity relationship studies whereas an enantioselective organocatalytic nitro-Mannich reaction enabled the synthesis of the lead scaffold in enantioenriched form and on scale. This epigenetic probe was shown to inhibit the association of BRD7 and BRD9 to acetylated histones in vitro and in cells. Moreover, LP99 was used to demonstrate that BRD7/9 plays a role in regulating pro-inflammatory cytokine secretion.


  • Organizational Affiliation

    Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA (UK).


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bromodomain-containing protein 9
A, B
123Homo sapiensMutation(s): 0 
Gene Names: BRD9UNQ3040/PRO9856
UniProt & NIH Common Fund Data Resources
Find proteins for Q9H8M2 (Homo sapiens)
Explore Q9H8M2 
Go to UniProtKB:  Q9H8M2
PHAROS:  Q9H8M2
GTEx:  ENSG00000028310 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9H8M2
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
4L3
Query on 4L3

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
tert-butyl [(2R,3S)-1-(1,4-dimethyl-2-oxo-1,2-dihydroquinolin-7-yl)-6-oxo-2-phenylpiperidin-3-yl]carbamate
C27 H31 N3 O4
SMDVXOGKDHVOGV-SQJMNOBHSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
4L3 BindingDB:  4Z6I Kd: 493 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.184 
  • Space Group: I 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 60.015α = 90
b = 29.458β = 92.24
c = 141.187γ = 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: 2015-05-20
    Type: Initial release
  • Version 1.1: 2024-01-10
    Changes: Data collection, Database references, Refinement description