5DBM

Crystal structure of the CBP bromodomain in complex with CPI703


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.86 Å
  • R-Value Free: 0.220 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.175 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Regulatory T Cell Modulation by CBP/EP300 Bromodomain Inhibition.

Ghosh, S.Taylor, A.Chin, M.Huang, H.R.Conery, A.R.Mertz, J.A.Salmeron, A.Dakle, P.J.Mele, D.Cote, A.Jayaram, H.Setser, J.W.Poy, F.Hatzivassiliou, G.DeAlmeida-Nagata, D.Sandy, P.Hatton, C.Romero, F.A.Chiang, E.Reimer, T.Crawford, T.Pardo, E.Watson, V.G.Tsui, V.Cochran, A.G.Zawadzke, L.Harmange, J.C.Audia, J.E.Bryant, B.M.Cummings, R.T.Magnuson, S.R.Grogan, J.L.Bellon, S.F.Albrecht, B.K.Sims, R.J.Lora, J.M.

(2016) J Biol Chem 291: 13014-13027

  • DOI: https://doi.org/10.1074/jbc.M115.708560
  • Primary Citation of Related Structures:  
    4YK0, 5DBM

  • PubMed Abstract: 

    Covalent modification of histones is a fundamental mechanism of regulated gene expression in eukaryotes, and interpretation of histone modifications is an essential feature of epigenetic control. Bromodomains are specialized binding modules that interact with acetylated histones, linking chromatin recognition to gene transcription. Because of their ability to function in a domain-specific fashion, selective disruption of bromodomain:acetylated histone interactions with chemical probes serves as a powerful means for understanding biological processes regulated by these chromatin adaptors. Here we describe the discovery and characterization of potent and selective small molecule inhibitors for the bromodomains of CREBBP/EP300 that engage their target in cellular assays. We use these tools to demonstrate a critical role for CREBBP/EP300 bromodomains in regulatory T cell biology. Because regulatory T cell recruitment to tumors is a major mechanism of immune evasion by cancer cells, our data highlight the importance of CREBBP/EP300 bromodomain inhibition as a novel, small molecule-based approach for cancer immunotherapy.


  • Organizational Affiliation

    From the Constellation Pharmaceuticals, Inc., Massachusetts 02142 and.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
CREB-binding protein
A, B, C
118Homo sapiensMutation(s): 0 
Gene Names: CREBBPCBP
EC: 2.3.1.48
UniProt & NIH Common Fund Data Resources
Find proteins for Q92793 (Homo sapiens)
Explore Q92793 
Go to UniProtKB:  Q92793
PHAROS:  Q92793
GTEx:  ENSG00000005339 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ92793
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
58N
Query on 58N

Download Ideal Coordinates CCD File 
D [auth A],
E [auth B],
F [auth C]
(4R)-6-(1-tert-butyl-1H-pyrazol-4-yl)-4-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one
C17 H22 N4 O
HPSNXSAYALRMQW-LLVKDONJSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
58N Binding MOAD:  5DBM Kd: 350 (nM) from 1 assay(s)
BindingDB:  5DBM IC50: min: 456, max: 470 (nM) from 2 assay(s)
EC50: 2100 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.86 Å
  • R-Value Free: 0.220 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.175 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 110.588α = 90
b = 34.034β = 103.93
c = 117.727γ = 90
Software Package:
Software NamePurpose
HKL-2000data scaling
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-04-20
    Type: Initial release
  • Version 1.1: 2016-06-29
    Changes: Database references
  • Version 1.2: 2023-09-27
    Changes: Data collection, Database references, Derived calculations, Refinement description