4C5D

Crystal structure of Bcl-xL in complex with benzoylurea compound (42)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.242 
  • R-Value Work: 0.166 
  • R-Value Observed: 0.170 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

De-Novo Designed Library of Benzoylureas as Inhibitors of Bcl-Xl: Synthesis, Structural and Biochemical Characterization.

Brady, R.M.Vom, A.Roy, M.J.Toovey, N.Smith, B.J.Moss, R.M.Hazis, E.Huang, D.C.S.Parisot, J.P.Yang, H.Street, I.P.Colman, P.M.Czabotar, P.E.Baell, J.B.Lessene, G.

(2014) J Med Chem 57: 1323

  • DOI: https://doi.org/10.1021/jm401948b
  • Primary Citation of Related Structures:  
    4C52, 4C5D

  • PubMed Abstract: 

    The prosurvival BCL-2 proteins are attractive yet challenging targets for medicinal chemists. Their involvement in the initiation and progression of many, if not all, tumors makes them prime targets for developing new anticancer therapies. We present our approach based on de novo structure-based drug design. Using known structural information from complexes engaging opposing members of the BCL-2 family of proteins, we designed peptidomimetic compounds using a benzoylurea scaffold to reproduce key interactions between these proteins. A library stemming from the initial de novo designed scaffold led to the discovery of ligands with low micromolar potency (KD = 4 μM) and selectivity for BCL-XL. These compounds bind in the canonical BH3 binding groove in a binding mode distinct from previously known BCL-2 inhibitors. The results of our study provide insight into the design of a new class of antagonists targeting a challenging class of protein-protein interactions.


  • Organizational Affiliation

    The Walter and Eliza Hall Institute of Medical Research , 1G Royal Parade, Parkville, Victoria 3052, Australia.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
BCL-2-LIKE PROTEIN 1
A, B
158Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for Q07817 (Homo sapiens)
Explore Q07817 
Go to UniProtKB:  Q07817
PHAROS:  Q07817
GTEx:  ENSG00000171552 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ07817
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
X0R
Query on X0R

Download Ideal Coordinates CCD File 
C [auth A],
L [auth B]
(R)-3-(4-BROMOBENZYLTHIO)-2-(3-(3-((2,4-DIFLUOROPHENYL)ETHYNYL)BENZOYL)-3-PROPYLUREIDO)PROPANOIC ACID
C29 H25 Br F2 N2 O4 S
WDPWVHPOPPOGPB-SANMLTNESA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
D [auth A]
E [auth A]
F [auth A]
M [auth B]
N [auth B]
D [auth A],
E [auth A],
F [auth A],
M [auth B],
N [auth B],
O [auth B]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
EDO
Query on EDO

Download Ideal Coordinates CCD File 
G [auth A]
H [auth A]
I [auth A]
J [auth A]
K [auth A]
G [auth A],
H [auth A],
I [auth A],
J [auth A],
K [auth A],
P [auth B],
Q [auth B],
R [auth B],
S [auth B],
T [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
X0R Binding MOAD:  4C5D Kd: 4000 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.242 
  • R-Value Work: 0.166 
  • R-Value Observed: 0.170 
  • Space Group: P 32 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 64.138α = 90
b = 64.138β = 90
c = 132.376γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
SCALAdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-02-05
    Type: Initial release
  • Version 1.1: 2014-03-12
    Changes: Database references
  • Version 1.2: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description