6DMJ

A multiconformer ligand model of inhibitor 53W bound to CREB binding protein bromodomain


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.15 Å
  • R-Value Free: 0.194 
  • R-Value Work: 0.158 
  • R-Value Observed: 0.160 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history

Re-refinement Note

This entry reflects an alternative modeling of the original data in: 5CFW


Literature

qFit-ligand Reveals Widespread Conformational Heterogeneity of Drug-Like Molecules in X-Ray Electron Density Maps.

van Zundert, G.C.P.Hudson, B.M.de Oliveira, S.H.P.Keedy, D.A.Fonseca, R.Heliou, A.Suresh, P.Borrelli, K.Day, T.Fraser, J.S.van den Bedem, H.

(2018) J Med Chem 61: 11183-11198

  • DOI: https://doi.org/10.1021/acs.jmedchem.8b01292
  • Primary Citation of Related Structures:  
    6DMG, 6DMH, 6DMI, 6DMJ, 6DMK, 6DML

  • PubMed Abstract: 

    Proteins and ligands sample a conformational ensemble that governs molecular recognition, activity, and dissociation. In structure-based drug design, access to this conformational ensemble is critical to understand the balance between entropy and enthalpy in lead optimization. However, ligand conformational heterogeneity is currently severely underreported in crystal structures in the Protein Data Bank, owing in part to a lack of automated and unbiased procedures to model an ensemble of protein-ligand states into X-ray data. Here, we designed a computational method, qFit-ligand, to automatically resolve conformationally averaged ligand heterogeneity in crystal structures, and applied it to a large set of protein receptor-ligand complexes. In an analysis of the cancer related BRD4 domain, we found that up to 29% of protein crystal structures bound with drug-like molecules present evidence of unmodeled, averaged, relatively isoenergetic conformations in ligand-receptor interactions. In many retrospective cases, these alternate conformations were adventitiously exploited to guide compound design, resulting in improved potency or selectivity. Combining qFit-ligand with high-throughput screening or multitemperature crystallography could therefore augment the structure-based drug design toolbox.


  • Organizational Affiliation

    Schrödinger , New York , New York 10036 , United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bromodomain-containing protein 4127Homo sapiensMutation(s): 0 
Gene Names: BRD4HUNK1
UniProt & NIH Common Fund Data Resources
Find proteins for O60885 (Homo sapiens)
Explore O60885 
Go to UniProtKB:  O60885
PHAROS:  O60885
GTEx:  ENSG00000141867 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO60885
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
53W (Subject of Investigation/LOI)
Query on 53W

Download Ideal Coordinates CCD File 
B [auth A]5-(3,5-dimethyl-1,2-oxazol-4-yl)-2-[2-(4-methoxyphenyl)ethyl]-1-[2-(morpholin-4-yl)ethyl]-1H-benzimidazole
C27 H32 N4 O3
RQFUKBAHMUVXDA-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
53W BindingDB:  6DMJ Kd: 780 (nM) from 1 assay(s)
IC50: 2400 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.15 Å
  • R-Value Free: 0.194 
  • R-Value Work: 0.158 
  • R-Value Observed: 0.160 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 39.61α = 90
b = 50.27β = 90
c = 57.21γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
Aimlessdata scaling
BUSTERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2018-12-19
    Type: Initial release
  • Version 1.1: 2019-04-24
    Changes: Data collection, Database references
  • Version 1.2: 2024-03-13
    Changes: Data collection, Database references
  • Version 1.3: 2024-05-01
    Changes: Structure summary