3ZLO

Crystal structure of BCL-XL in complex with inhibitor (Compound 6)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.282 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.197 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 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: 390-397

  • 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 1181Homo 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
X8U
Query on X8U

Download Ideal Coordinates CCD File 
B [auth A]2-[(8E)-8-(1,3-benzothiazol-2-ylhydrazinylidene)-6,7-dihydro-5H-naphthalen-2-yl]-5-(4-phenylbutyl)-1,3-thiazole-4-carboxylic acid
C31 H28 N4 O2 S2
KJRCRYVHSPWAIC-JGRMKTMXSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
X8U PDBBind:  3ZLO IC50: 1.5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.282 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.197 
  • Space Group: P 32 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 67.832α = 90
b = 67.832β = 90
c = 67.383γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
DENZOdata reduction
SCALEPACKdata 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: 2018-06-13
    Changes: Data collection, Database references, Structure summary
  • Version 1.4: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description