PDBsum entry 2o22

Go to PDB code: 
protein ligands links
Apoptosis PDB id
Protein chain
164 a.a. *
* Residue conservation analysis
PDB id:
Name: Apoptosis
Title: Solution structure of the anti-apoptotic protein bcl-2 in co an acyl-sulfonamide-based ligand
Structure: Apoptosis regulator bcl-2. Chain: a. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: bcl2. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
NMR struc: 1 models
Authors: M.Bruncko,T.K.Oost,B.A.Belli,H.Ding,M.K.Joseph,A.Kunzer,D.Ma W.J.Mcclellan,M.Mitten,S.C.Ng,P.M.Nimmer,T.Oltersdorf,C.M.P A.M.Petros,A.R.Shoemaker,X.Song,X.Wang,M.D.Wendt,H.Zhang,S. S.H.Rosenberg,S.W.Elmore
Key ref: M.Bruncko et al. (2007). Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL. J Med Chem, 50, 641-662. PubMed id: 17256834 DOI: 10.1021/jm061152t
29-Nov-06     Release date:   27-Feb-07    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P10415  (BCL2_HUMAN) -  Apoptosis regulator Bcl-2
239 a.a.
164 a.a.*
Key:    PfamA domain  Secondary structure
* PDB and UniProt seqs differ at 14 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     regulation of apoptotic process   2 terms 


DOI no: 10.1021/jm061152t J Med Chem 50:641-662 (2007)
PubMed id: 17256834  
Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL.
M.Bruncko, T.K.Oost, B.A.Belli, H.Ding, M.K.Joseph, A.Kunzer, D.Martineau, W.J.McClellan, M.Mitten, S.C.Ng, P.M.Nimmer, T.Oltersdorf, C.M.Park, A.M.Petros, A.R.Shoemaker, X.Song, X.Wang, M.D.Wendt, H.Zhang, S.W.Fesik, S.H.Rosenberg, S.W.Elmore.
Overexpression of the antiapototic proteins Bcl-2 and Bcl-xL provides a common mechanism through which cancer cells gain a survival advantage and become resistant to conventional chemotherapy. Inhibition of these prosurvival proteins is an attractive strategy for cancer therapy. We recently described the discovery of a selective Bcl-xL antagonist that potentiates the antitumor activity of chemotherapy and radiation. Here we describe the use of structure-guided design to exploit a deep hydrophobic binding pocket on the surface of these proteins to develop the first dual, subnanomolar inhibitors of Bcl-xL and Bcl-2. This study culminated in the identification of 2, which exhibited EC50 values of 8 nM and 30 nM in Bcl-2 and Bcl-xL dependent cells, respectively. Compound 2 demonstrated single agent efficacy against human follicular lymphoma cell lines that overexpress Bcl-2, and efficacy in a murine xenograft model of lymphoma when given both as a single agent and in combination with etoposide.

Literature references that cite this PDB file's key reference

  PubMed id Reference
21103609 F.P.Davis (2011).
Proteome-wide prediction of overlapping small molecule and protein binding sites using structure.
  Mol Biosyst, 7, 545-557.  
21056595 J.Lindsay, M.D.Esposti, and A.P.Gilmore (2011).
Bcl-2 proteins and mitochondria--specificity in membrane targeting for death.
  Biochim Biophys Acta, 1813, 532-539.  
20407211 S.M.Massa, T.Yang, Y.Xie, J.Shi, M.Bilgen, J.N.Joyce, D.Nehama, J.Rajadas, and F.M.Longo (2010).
Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents.
  J Clin Invest, 120, 1774-1785.  
20309488 X.Hu, and R.Manetsch (2010).
Kinetic target-guided synthesis.
  Chem Soc Rev, 39, 1316-1324.  
19066994 A.M.Almerico, M.Tutone, and A.Lauria (2009).
In-silico screening of new potential Bcl-2/Bcl-xl inhibitors as apoptosis modulators.
  J Mol Model, 15, 349-355.  
19726685 E.F.Lee, P.E.Czabotar, H.Yang, B.E.Sleebs, G.Lessene, P.M.Colman, B.J.Smith, and W.D.Fairlie (2009).
Conformational changes in Bcl-2 pro-survival proteins determine their capacity to bind ligands.
  J Biol Chem, 284, 30508-30517.
PDB codes: 3io8 3io9
19263447 J.M.Rodriguez, L.Nevola, N.T.Ross, G.I.Lee, and A.D.Hamilton (2009).
Synthetic inhibitors of extended helix-protein interactions based on a biphenyl 4,4'-dicarboxamide scaffold.
  Chembiochem, 10, 829-833.  
19555126 J.Wei, S.Kitada, M.F.Rega, J.L.Stebbins, D.Zhai, J.Cellitti, H.Yuan, A.Emdadi, R.Dahl, Z.Zhang, L.Yang, J.C.Reed, and M.Pellecchia (2009).
Apogossypol derivatives as pan-active inhibitors of antiapoptotic B-cell lymphoma/leukemia-2 (Bcl-2) family proteins.
  J Med Chem, 52, 4511-4523.  
19028598 M.Orita, K.Ohno, and T.Niimi (2009).
Two 'Golden Ratio' indices in fragment-based drug discovery.
  Drug Discov Today, 14, 321-328.  
18806758 M.Vogler, D.Dinsdale, M.J.Dyer, and G.M.Cohen (2009).
Bcl-2 inhibitors: small molecules with a big impact on cancer therapy.
  Cell Death Differ, 16, 360-367.  
19390557 M.Vogler, K.Weber, D.Dinsdale, I.Schmitz, K.Schulze-Osthoff, M.J.Dyer, and G.M.Cohen (2009).
Different forms of cell death induced by putative BCL2 inhibitors.
  Cell Death Differ, 16, 1030-1039.  
19242522 R.Soltani-Arabshahi, C.Leboeuf, J.Rivet, H.Pisonero, W.L.Zhao, H.Bachelez, J.C.Ameisen, and A.Janin (2009).
Bcl-xL gene expression correlated with lower apoptotic cell numbers and shorter progression-free survival in PCFCL.
  J Invest Dermatol, 129, 1703-1709.  
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.  
18275607 A.A.Arnold, A.Aboukameel, J.Chen, D.Yang, S.Wang, A.Al-Katib, and R.M.Mohammad (2008).
Preclinical studies of Apogossypolone: a new nonpeptidic pan small-molecule inhibitor of Bcl-2, Bcl-XL and Mcl-1 proteins in Follicular Small Cleaved Cell Lymphoma model.
  Mol Cancer, 7, 20.  
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.  
19043450 G.Lessene, P.E.Czabotar, and P.M.Colman (2008).
BCL-2 family antagonists for cancer therapy.
  Nat Rev Drug Discov, 7, 989.  
18467496 M.D.Boersma, J.D.Sadowsky, Y.A.Tomita, and S.H.Gellman (2008).
Hydrophile scanning as a complement to alanine scanning for exploring and manipulating protein-protein recognition: application to the Bim BH3 domain.
  Protein Sci, 17, 1232-1240.  
19012295 S.Kneissl, E.J.Loveridge, C.Williams, M.P.Crump, and R.K.Allemann (2008).
Photocontrollable peptide-based switches target the anti-apoptotic protein Bcl-xL.
  Chembiochem, 9, 3046-3054.  
17572662 E.F.Lee, P.E.Czabotar, B.J.Smith, K.Deshayes, K.Zobel, P.M.Colman, and W.D.Fairlie (2007).
Crystal structure of ABT-737 complexed with Bcl-xL: implications for selectivity of antagonists of the Bcl-2 family.
  Cell Death Differ, 14, 1711-1713.
PDB code: 2yxj
17665978 H.Hagland, J.Nikolaisen, L.I.Hodneland, B.T.Gjertsen, ..Bruserud, and K.J.Tronstad (2007).
Targeting mitochondria in the treatment of human cancer: a coordinated attack against cancer cell energy metabolism and signalling.
  Expert Opin Ther Targets, 11, 1055-1069.  
18075579 J.A.Wells, and C.L.McClendon (2007).
Reaching for high-hanging fruit in drug discovery at protein-protein interfaces.
  Nature, 450, 1001-1009.  
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.  
17921043 L.Zhang, L.Ming, and J.Yu (2007).
BH3 mimetics to improve cancer therapy; mechanisms and examples.
  Drug Resist Updat, 10, 207-217.  
18040043 M.Nguyen, R.C.Marcellus, A.Roulston, M.Watson, L.Serfass, S.R.Murthy Madiraju, D.Goulet, J.Viallet, L.Bélec, X.Billot, S.Acoca, E.Purisima, A.Wiegmans, L.Cluse, R.W.Johnstone, P.Beauparlant, and G.C.Shore (2007).
Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis.
  Proc Natl Acad Sci U S A, 104, 19512-19517.  
17597151 X.Fu, J.R.Apgar, and A.E.Keating (2007).
Modeling backbone flexibility to achieve sequence diversity: the design of novel alpha-helical ligands for Bcl-xL.
  J Mol Biol, 371, 1099-1117.  
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.