7VRI

crystal structure of BRD2-BD2 in complex with guanosine analog


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.50 Å
  • R-Value Free: 0.228 
  • R-Value Work: 0.183 
  • R-Value Observed: 0.185 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structural and biochemical insights into purine-based drug molecules in hBRD2 delineate a unique binding mode opening new vistas in the design of inhibitors of the BET family.

Arole, A.H.Deshmukh, P.Sridhar, A.Mathur, S.Mahalingaswamy, M.Subramanya, H.Dalavaikodihalli Nanjaiah, N.Padmanabhan, B.

(2023) Acta Crystallogr D Struct Biol 79: 758-774

  • DOI: https://doi.org/10.1107/S2059798323005211
  • Primary Citation of Related Structures:  
    7VRH, 7VRI, 7VRK, 7VRM, 7VRO, 7VRQ, 7VRZ, 7VS0, 7VS1, 7VSF

  • PubMed Abstract: 

    The bromodomain and extra-terminal (BET) family proteins, which are involved in chromatin function, have been shown to be promising drug targets in several pathological conditions, including cancer and inflammation. There is considerable interest in the development of BET inhibitors with novel scaffolds to modulate the epigenesis of such diseases. Here, high-resolution crystal structures of the purine class of FDA-approved drugs (theophylline, doxophylline and acyclovir) and non-FDA-approved compounds (3-methyl-7-propylxanthine and theobromine) complexed with hBRD2 bromodomains BD1 and BD2 are reported. Remarkably, a new binding site is exhibited by stacking the compounds against the WPF shelf of BD1 and BD2. This serendipitous binding, in addition to the known acetyl-lysine binding site, sufficiently anchors the ligands in the solvent-exposed region. In addition, slight variations in the lipophilicity of these molecules significantly affected the in vitro binding affinity and selectivity towards BD1 compared with BD2. This idiosyncratic binding provides a new structural framework to link these sites for the development of next-generation inhibitors of the BET family.


  • Organizational Affiliation

    Department of Biophysics, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Main Road, Bengaluru 560029, India.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bromodomain-containing protein 2115Homo sapiensMutation(s): 2 
Gene Names: BRD2
UniProt & NIH Common Fund Data Resources
Find proteins for P25440 (Homo sapiens)
Explore P25440 
Go to UniProtKB:  P25440
PHAROS:  P25440
GTEx:  ENSG00000204256 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP25440
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
AC2 (Subject of Investigation/LOI)
Query on AC2

Download Ideal Coordinates CCD File 
B [auth A]9-HYROXYETHOXYMETHYLGUANINE
C8 H11 N5 O3
MKUXAQIIEYXACX-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.50 Å
  • R-Value Free: 0.228 
  • R-Value Work: 0.183 
  • R-Value Observed: 0.185 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 52.316α = 90
b = 71.476β = 90
c = 32.028γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-3000data reduction
HKL-3000data scaling
PHENIXphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Not funded--

Revision History  (Full details and data files)

  • Version 1.0: 2023-02-01
    Type: Initial release
  • Version 1.1: 2023-08-02
    Changes: Database references
  • Version 1.2: 2023-08-16
    Changes: Data collection, Database references
  • Version 1.3: 2023-11-29
    Changes: Refinement description