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PDBsum entry 1r2e

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Apoptosis PDB id
1r2e
Jmol
Contents
Protein chain
143 a.a. *
Waters ×138
* Residue conservation analysis
PDB id:
1r2e
Name: Apoptosis
Title: Human bcl-xl containing a glu to leu mutation at position 92
Structure: Apoptosis regulator bcl-x. Chain: a. Fragment: bcl-xl. Synonym: bcl-2-like 1 protein. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: bcl-xl. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Resolution:
2.10Å     R-factor:   0.212     R-free:   0.239
Authors: J.W.O'Neill,M.K.Manion,C.D.Giedt,K.M.Kim,K.Y.Zhang, D.M.Hockenbery
Key ref:
M.K.Manion et al. (2004). Bcl-XL mutations suppress cellular sensitivity to antimycin A. J Biol Chem, 279, 2159-2165. PubMed id: 14534311 DOI: 10.1074/jbc.M306021200
Date:
26-Sep-03     Release date:   03-Feb-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q07817  (B2CL1_HUMAN) -  Bcl-2-like protein 1
Seq:
Struc:
233 a.a.
143 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     synapse   21 terms 
  Biological process     nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway   46 terms 
  Biochemical function     protein binding     6 terms  

 

 
DOI no: 10.1074/jbc.M306021200 J Biol Chem 279:2159-2165 (2004)
PubMed id: 14534311  
 
 
Bcl-XL mutations suppress cellular sensitivity to antimycin A.
M.K.Manion, J.W.O'Neill, C.D.Giedt, K.M.Kim, K.Y.Zhang, D.M.Hockenbery.
 
  ABSTRACT  
 
Cells expressing high levels of the BCL-X(L) anti-apoptotic protein are preferentially killed by the mitochondrial inhibitor antimycin A (AA). Computational modeling predicts a binding site for AA in the extended hydrophobic groove on BCL-X(L), previously identified as an interface for dimerization to BAX and related proapoptotic proteins. Here, we identify BCL-X(L) hydrophobic groove mutants with normal cellular anti-apoptotic function but suppressed sensitivity to AA. The LD(50) of AA for cells expressing BCL-X(L) mutants directly correlates with the measured in vitro dissociation constants for AA binding. These results indicate that BCL-X(L) is a principal target mediating AA cytotoxicity.
 
  Selected figure(s)  
 
Figure 1.
FIG. 1. Position of BCL-X[L] hydrophobic groove mutations relative to predicted antimycin A[1] binding site. Molecular surface of BCL-X[L] with modeled antimycin A molecule. The Glu-92 (brown) carbonyl oxygen and side chains of Phe-97 (magenta), Ala-142 (purple), and Phe-146 (orange) contact antimycin A[1] in the docking model.
Figure 6.
FIG. 6. Alignments of side chain mutations on BCL-X[L]( C) structure (1BXL [PDB] ) used as docking target for AA[1]. a, alignments of BCL-X[L]( C) structure in free (green) and BAK-BH3-bound (black) conformations. The modeled AA[1] (light green) is shown in place of BAK-BH3 in binding pocket. The C RMSD for residues Glu-92, Phe-97, Ala-142, and Phe-146 is 1.3 Å, whereas overall C RMSD is 2.5 Å. b-d, modeling of mutations into hydrophobic groove of 1BXL [PDB] . Yellow stars indicate clashing contacts. b, F97W (purple) makes two moderate clashing contacts, each at 2.6 Å. c, the A142L mutation (magenta) makes an extreme clashing contact with CD1 to O8 of AA[1] at 1.2 Å. d, although Phe-146 makes two van der Waals contacts with the C27 of AA[1] the F146L mutation (orange) only makes one contact from CD1 (3.4 Å). Nitrogen atoms are colored blue, and oxygen atoms are colored red.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2004, 279, 2159-2165) copyright 2004.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20213841 D.M.Hockenbery (2010).
Targeting mitochondria for cancer therapy.
  Environ Mol Mutagen, 51, 476-489.  
  19229915 E.F.Lee, J.D.Sadowsky, B.J.Smith, P.E.Czabotar, K.J.Peterson-Kaufman, P.M.Colman, S.H.Gellman, and W.D.Fairlie (2009).
High-resolution structural characterization of a helical alpha/beta-peptide foldamer bound to the anti-apoptotic protein Bcl-xL.
  Angew Chem Int Ed Engl, 48, 4318-4322.
PDB codes: 3fdl 3fdm
19875081 F.Buller, Y.Zhang, J.Scheuermann, J.Schäfer, P.Bühlmann, and D.Neri (2009).
Discovery of TNF inhibitors from a DNA-encoded chemical library based on diels-alder cycloaddition.
  Chem Biol, 16, 1075-1086.  
  19411865 M.A.Fath, A.R.Diers, N.Aykin-Burns, A.L.Simons, L.Hua, and D.R.Spitz (2009).
Mitochondrial electron transport chain blockers enhance 2-deoxy-D-glucose induced oxidative stress and cell killing in human colon carcinoma cells.
  Cancer Biol Ther, 8, 1228-1236.  
19486669 S.Yang, S.Park, L.Makowski, and B.Roux (2009).
A rapid coarse residue-based computational method for x-ray solution scattering characterization of protein folds and multiple conformational states of large protein complexes.
  Biophys J, 96, 4449-4463.  
18780145 W.Novak, H.Wang, and G.Krilov (2009).
Role of protein flexibility in the design of Bcl-X(L) targeting agents: insight from molecular dynamics.
  J Comput Aided Mol Des, 23, 49-61.  
18757333 B.D.Zeitlin, I.J.Zeitlin, and J.E.Nör (2008).
Expanding circle of inhibition: small-molecule inhibitors of Bcl-2 as anticancer cell and antiangiogenic agents.
  J Clin Oncol, 26, 4180-4188.  
18719108 C.Katz, H.Benyamini, S.Rotem, M.Lebendiker, T.Danieli, A.Iosub, H.Refaely, M.Dines, V.Bronner, T.Bravman, D.E.Shalev, S.Rüdiger, and A.Friedler (2008).
Molecular basis of the interaction between the antiapoptotic Bcl-2 family proteins and the proapoptotic protein ASPP2.
  Proc Natl Acad Sci U S A, 105, 12277-12282.  
18452209 D.Lama, and R.Sankararamakrishnan (2008).
Anti-apoptotic Bcl-XL protein in complex with BH3 peptides of pro-apoptotic Bak, Bad, and Bim proteins: comparative molecular dynamics simulations.
  Proteins, 73, 492-514.  
18955968 K.W.Yip, and J.C.Reed (2008).
Bcl-2 family proteins and cancer.
  Oncogene, 27, 6398-6406.  
17654739 J.L.Mott, and G.J.Gores (2007).
Piercing the armor of hepatobiliary cancer: Bcl-2 homology domain 3 (BH3) mimetics and cell death.
  Hepatology, 46, 906-911.  
15899920 M.M.Rhodes, P.Kopsombut, M.C.Bondurant, J.O.Price, and M.J.Koury (2005).
Bcl-x(L) prevents apoptosis of late-stage erythroblasts but does not mediate the antiapoptotic effect of erythropoietin.
  Blood, 106, 1857-1863.  
15123233 D.Hockenbery (2004).
Breaking down tumor defenses.
  Chem Biol, 11, 417-418.  
15585172 J.O'Neill, M.Manion, P.Schwartz, and D.M.Hockenbery (2004).
Promises and challenges of targeting Bcl-2 anti-apoptotic proteins for cancer therapy.
  Biochim Biophys Acta, 1705, 43-51.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.