5EJW

Crystal structure of chromobox homolog 7 (CBX7) chromodomain with MS351


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.237 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.196 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structure-Guided Discovery of Selective Antagonists for the Chromodomain of Polycomb Repressive Protein CBX7.

Ren, C.Smith, S.G.Yap, K.Li, S.Li, J.Mezei, M.Rodriguez, Y.Vincek, A.Aguilo, F.Walsh, M.J.Zhou, M.M.

(2016) ACS Med Chem Lett 7: 601-605

  • DOI: https://doi.org/10.1021/acsmedchemlett.6b00042
  • Primary Citation of Related Structures:  
    5EJW

  • PubMed Abstract: 

    The chromobox 7 (CBX7) protein of the polycomb repressive complex 1 (PRC1) functions to repress transcription of tumor suppressor p16 (INK4a) through long noncoding RNA, ANRIL (antisense noncoding RNA in the INK4 locus) directed chromodomain (ChD) binding to trimethylated lysine 27 of histone H3 (H3K27me3), resulting in chromatin compaction at the INK4a/ARF locus. In this study, we report structure-guided discovery of two distinct classes of small-molecule antagonists for the CBX7ChD. Our Class A compounds, a series including analogues of the previously reported MS452, inhibit CBX7ChD/methyl-lysine binding by occupying the H3K27me3 peptide binding site, whereas our Class B compound, the newly discovered MS351, appears to inhibit H3K27me3 binding when CBX7ChD is bound to RNA. Our crystal structure of the CBX7ChD/MS351 complex reveals the molecular details of ligand recognition by the aromatic cage residues that typically engage in methyl-lysine binding. We further demonstrate that MS351 effectively induces transcriptional derepression of CBX7 target genes, including p16 (INK4a) in mouse embryonic stem cells and human prostate cancer PC3 cells. Thus, MS351 represents a new class of ChD antagonists that selectively targets the biologically active form of CBX7 of the PRC1 in long noncoding RNA- and H3K27me3-directed gene transcriptional repression.


  • Organizational Affiliation

    Department of Structural and Chemical Biology and Department of Pediatrics, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Chromobox protein homolog 791Mus musculusMutation(s): 0 
Gene Names: Cbx7D15Ertd417e
UniProt
Find proteins for Q8VDS3 (Mus musculus)
Explore Q8VDS3 
Go to UniProtKB:  Q8VDS3
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ8VDS3
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
5PZ
Query on 5PZ

Download Ideal Coordinates CCD File 
B [auth A](1~{R})-2-[2-azanylidene-3-[(2-methylphenyl)methyl]benzimidazol-1-yl]-1-(3,4-dichlorophenyl)ethanol
C23 H21 Cl2 N3 O
BEKCHDAUQRKKOP-NFLAHJKKSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
5PZ BindingDB:  5EJW Kd: min: 2.38e+4, max: 5.00e+5 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.237 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.196 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 52.748α = 90
b = 52.748β = 90
c = 76.813γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling
BALBESphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-03-09
    Type: Initial release
  • Version 1.1: 2016-07-06
    Changes: Database references
  • Version 1.2: 2023-09-27
    Changes: Data collection, Database references, Derived calculations, Refinement description