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PDBsum entry 3zlr

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protein ligands Protein-protein interface(s) links
Apoptosis PDB id
3zlr
Jmol
Contents
Protein chains
146 a.a.
Ligands
X0B ×2
EDO ×2
SO4 ×3
Waters ×262
PDB id:
3zlr
Name: Apoptosis
Title: Crystal structure of bcl-xl in complex with inhibitor (wehi- 539).
Structure: Bcl-2-like protein 1. Chain: a, b. Fragment: residues 1-26,83-209. Synonym: bcl2-l-1, apoptosis regulator bcl-x, bcl-xl. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 511693.
Resolution:
2.03Å     R-factor:   0.160     R-free:   0.208
Authors: P.E.Czabotar,G.L.Lessene,B.J.Smith,P.M.Colman
Key ref: G.Lessene et al. (2013). Structure-guided design of a selective BCL-X(L) inhibitor. Nat Chem Biol, 9, 390-397. PubMed id: 23603658 DOI: 10.1038/nchembio.1246
Date:
04-Feb-13     Release date:   24-Apr-13    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q07817  (B2CL1_HUMAN) -  Bcl-2-like protein 1
Seq:
Struc:
233 a.a.
146 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     regulation of apoptotic process   1 term 

 

 
DOI no: 10.1038/nchembio.1246 Nat Chem Biol 9:390-397 (2013)
PubMed id: 23603658  
 
 
Structure-guided design of a selective BCL-X(L) inhibitor.
G.Lessene, P.E.Czabotar, B.E.Sleebs, K.Zobel, K.N.Lowes, J.M.Adams, J.B.Baell, P.M.Colman, K.Deshayes, W.J.Fairbrother, J.A.Flygare, P.Gibbons, W.J.Kersten, S.Kulasegaram, R.M.Moss, J.P.Parisot, B.J.Smith, I.P.Street, H.Yang, D.C.Huang, K.G.Watson.
 
  ABSTRACT  
 
The prosurvival BCL-2 family protein BCL-XL is often overexpressed in solid tumors and renders malignant tumor cells resistant to anticancer therapeutics. Enhancing apoptotic responses by inhibiting BCL-XL will most likely have widespread utility in cancer treatment and, instead of inhibiting multiple prosurvival BCL-2 family members, a BCL-XL-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-XL and their structure-guided development by medicinal chemistry. The optimized compound, WEHI-539 (7), has high affinity (subnanomolar) and selectivity for BCL-XL and potently kills cells by selectively antagonizing its prosurvival activity. WEHI-539 will be an invaluable tool for distinguishing the roles of BCL-XL 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-XL for their sustained growth.