3ZK6

Crystal structure of Bcl-xL in complex with inhibitor (Compound 2).


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.48 Å
  • R-Value Free: 0.261 
  • R-Value Work: 0.221 
  • R-Value Observed: 0.222 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structure-Guided Design of a Selective Bcl-Xl Inhibitor

Lessene, G.L.Czabotar, P.E.Sleebs, B.E.Zobel, K.Lowes, K.L.Adams, J.M.Baell, J.B.Colman, P.M.Deshayes, K.Fairbrother, W.J.Flygare, J.A.Gibbons, P.Kersten, W.J.A.Kulasegaram, S.Moss, R.M.Parisot, J.P.Smith, B.J.Street, I.P.Yang, H.Huang, D.C.S.Watson, K.G.

(2013) Nat Chem Biol 9: 390

  • DOI: https://doi.org/10.1038/nchembio.1246
  • Primary Citation of Related Structures:  
    3ZK6, 3ZLN, 3ZLO, 3ZLR

  • PubMed Abstract: 

    The prosurvival BCL-2 family protein BCL-X(L) is often overexpressed in solid tumors and renders malignant tumor cells resistant to anticancer therapeutics. Enhancing apoptotic responses by inhibiting BCL-X(L) will most likely have widespread utility in cancer treatment and, instead of inhibiting multiple prosurvival BCL-2 family members, a BCL-X(L)-selective inhibitor would be expected to minimize the toxicity to normal tissues. We describe the use of a high-throughput screen to discover a new series of small molecules targeting BCL-X(L) and their structure-guided development by medicinal chemistry. The optimized compound, WEHI-539 (7), has high affinity (subnanomolar) and selectivity for BCL-X(L) and potently kills cells by selectively antagonizing its prosurvival activity. WEHI-539 will be an invaluable tool for distinguishing the roles of BCL-X(L) from those of its prosurvival relatives, both in normal cells and notably in malignant tumor cells, many of which may prove to rely upon BCL-X(L) for their sustained growth.


  • Organizational Affiliation

    Chemical Biology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. glessene@wehi.edu.au


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
BCL-2-LIKE PROTEIN 1
A, B
181Homo 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 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
H1I
Query on H1I

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
N-(3-(5-(1-(2-(benzo[d]thiazol-2-yl)hydrazono)ethyl)furan-2-yl)phenylsulfonyl)-6-phenylhexanamide
C31 H30 N4 O4 S2
ZGVBPNIFKPDHBC-STKMKYKTSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
H1I PDBBind:  3ZK6 Kd: 460 (nM) from 1 assay(s)
Binding MOAD:  3ZK6 Kd: 460 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.48 Å
  • R-Value Free: 0.261 
  • R-Value Work: 0.221 
  • R-Value Observed: 0.222 
  • Space Group: P 41
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 65.2α = 90
b = 65.2β = 90
c = 117.21γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XDSdata scaling
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: 2013-04-24
    Type: Initial release
  • Version 1.1: 2013-05-08
    Changes: Database references
  • Version 1.2: 2013-06-05
    Changes: Database references
  • Version 1.3: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description