Conformational Changes in Bcl-2 Pro-survival Proteins Determine Their Capacity to Bind Ligands

Lee, Erinna F.; Czabotar, P.E.; Yang, Hong; Sleebs, Brad E.; Lessène, Guillaume; Colman, Peter M.; Smith, Brian J.; Fairlie, W. Douglas

doi:10.1074/jbc.m109.040725

Cited by 81 publications

(98 citation statements)

References 61 publications

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“…The four signature hydrophobic residues of the Bak BH3 domain are buried within the groove (Fig. S5B), as in all previously determined BH3:prosurvival protein complexes (2)(3)(4)(5)27), and a salt bridge between a critical aspartyl residue on the peptide and an arginyl residue on the BH1 domain of the prosurvival protein, is also evident (Fig. S5C).…”

Section: Cellular Activity Of Proapoptotic Schistosome Bcl-2 Family Msupporting

confidence: 80%

“…Because BH3 mimetics function by engaging prosurvival proteins, we examined the ability of ABT-737 (the best characterized BH3 mimetic to date) to bind to sjA. Indeed, ABT-737 binds sjA with moderate affinity (IC 50 170 nM), whereas a closely related analog, W1191542 (27), binds significantly weaker (IC 50 5 μM), suggesting a highly specific interaction (Fig. 4A).…”

Section: Cellular Activity Of Proapoptotic Schistosome Bcl-2 Family Mmentioning

confidence: 99%

“…Experiments examining the effect of ABT-737 treatment on adult schistosomes in culture have provided variable results thus far, although in several experiments accelerated parasite death has been observed (at 20 μM) compared with parasites treated with the closely related, weaker binding analog W1191542 (27).…”

Section: Cellular Activity Of Proapoptotic Schistosome Bcl-2 Family Mmentioning

confidence: 99%

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Discovery and molecular characterization of a Bcl-2–regulated cell death pathway in schistosomes

Lee

Clarke

Evangelista

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Schistosomiasis is an infectious disease caused by parasites of the phylum platyhelminthe. Here, we describe the identification and characterization of a Bcl-2-regulated apoptosis pathway in Schistosoma japonicum and S. mansoni. Genomic, biochemical, and cellbased mechanistic studies provide evidence for a tripartite pathway, similar to that in humans including BH3-only proteins that are inhibited by prosurvival Bcl-2-like molecules, and Bax/Bak-like proteins that facilitate mitochondrial outer-membrane permeabilization. Because Bcl-2 proteins have been successfully targeted with "BH3 mimetic" drugs, particularly in the treatment of cancer, we investigated whether schistosome apoptosis pathways could provide targets for future antischistosomal drug discovery efforts. Accordingly, we showed that a schistosome prosurvival protein, sjA, binds ABT-737, a well-characterized BH3 mimetic. A crystal structure of sjA bound to a BH3 peptide provides direct evidence for the feasibility of developing BH3 mimetics to target Bcl-2 prosurvival proteins in schistosomes, suggesting an alternative application for this class of drugs beyond cancer treatment.

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Section: Cellular Activity Of Proapoptotic Schistosome Bcl-2 Family Msupporting

confidence: 80%

Section: Cellular Activity Of Proapoptotic Schistosome Bcl-2 Family Mmentioning

confidence: 99%

Section: Cellular Activity Of Proapoptotic Schistosome Bcl-2 Family Mmentioning

confidence: 99%

See 1 more Smart Citation

Discovery and molecular characterization of a Bcl-2–regulated cell death pathway in schistosomes

Lee

Clarke

Evangelista

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…This could lead in turn to increased availability of free Bim for Mcl-1 binding in such cell types. However, other explanations cannot be excluded, including the possibility that drug treatment could directly affect the binding capacity between Bim and different antiapoptotic proteins (e.g., Bcl-2, Bcl-x L , and Mcl-1) that exhibit significant differences in the structural properties responsible for binding of BH3-only proteins including Bim (42). On the other hand, treatment with ABT-737 alone led to a slight decrease in amount of Bim coimmunoprecipitated by Mcl-1 in U937 cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

Bim Upregulation by Histone Deacetylase Inhibitors Mediates Interactions with the Bcl-2 Antagonist ABT-737: Evidence for Distinct Roles for Bcl-2, Bcl-x_L, and Mcl-1

Chen¹,

Dai²,

Pei³

et al. 2009

Molecular and Cellular Biology

124

114

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The Bcl-2 antagonist ABT-737 kills transformed cells in association with displacement of Bim from Bcl-2. The histone deactetylase (HDAC) inhibitor suberoyl bis-hydroxamic acid (SBHA) was employed to determine whether and by what mechanism ABT-737 might interact with agents that upregulate Bim. Expression profiling of BH3-only proteins indicated that SBHA increased Bim, Puma, and Noxa expression, while SBHA concentrations that upregulated Bim significantly potentiated ABT-737 lethality. Concordance between SBHA-mediated Bim upregulation and interactions with ABT-737 was observed in various human leukemia and myeloma cells. SBHA-induced Bim was largely sequestered by Bcl-2 and Bcl-xL, rather than Mcl-1; ABT-737 attenuated these interactions, thereby triggering Bak/Bax activation and mitochondrial outer membrane permeabilization. Knockdown of Bim (but not Puma or Noxa) by shRNA or ectopic overexpression of Bcl-2, Bcl-xL, or Mcl-1 diminished Bax/Bak activation and apoptosis. Notably, ectopic expression of these antiapoptotic proteins disabled death signaling by sequestering different proapoptotic proteins, i.e., Bim by Bcl-2, both Bim and Bak by Bcl-xL, and Bak by Mcl-1. Together, these findings indicate that HDAC inhibitor-inducible Bim is primarily neutralized by Bcl-2 and Bcl-xL, thus providing a mechanistic framework by which Bcl-2 antagonists potentiate the lethality of agents, such as HDAC inhibitors, which upregulate Bim.

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“…48 At the periphery of proteins and solventexposed, interfaces are less subject to structural constraints, and Bcl-xL proved to be particularly flexible. 49 , 50 Transient pocket may also form on these surfaces. 51 Structural studies with Bcl-xL have shown that PPI inhibitors bind the large crevice receiving BH3 peptides, acting as competitive inhibitors.…”

Section: Resultsmentioning

confidence: 99%

A combination of in silico and SAR studies to identify binding hot spots of Bcl-xL inhibitors

Levoin

Gautier

et al. 2015

Bioorganic & Medicinal Chemistry

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To test if small and chemically diverse Bcl-xL inhibitors are likely to bind a single pocket, and to identify which pocket, we used a battery of computational and modeling approaches. We first checked that the large dataset of Bcl-xL inhibitors we built can actually fit to a universal pharmacophore. Then we defined the probable binding hot spots of interaction through comparison of crystal structures, as well as virtual fragment screening. Finally, new analogues of small polyphenol derivatives were synthesized to precisely probe a hydrogen bond suggested by docking experiments. Bcl-xL inhibition potency of these products confirmed the predicted binding mode. This combination of X-ray structure exploration, molecular modeling studies and medicinal chemistry supports that all these small Bcl-xL inhibitors occupy the same hot spot of interaction. The identification of this binding site should help the design and optimization of small PPI Bcl-xL inhibitors.

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Conformational Changes in Bcl-2 Pro-survival Proteins Determine Their Capacity to Bind Ligands

Abstract: Antagonists of anti-apoptotic

Cited by 81 publications

References 61 publications

Discovery and molecular characterization of a Bcl-2–regulated cell death pathway in schistosomes

Discovery and molecular characterization of a Bcl-2–regulated cell death pathway in schistosomes

Bim Upregulation by Histone Deacetylase Inhibitors Mediates Interactions with the Bcl-2 Antagonist ABT-737: Evidence for Distinct Roles for Bcl-2, Bcl-x_L, and Mcl-1

A combination of in silico and SAR studies to identify binding hot spots of Bcl-xL inhibitors

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Conformational Changes in Bcl-2 Pro-survival Proteins Determine Their Capacity to Bind Ligands

Abstract: Antagonists of anti-apoptotic

Cited by 81 publications

References 61 publications

Discovery and molecular characterization of a Bcl-2–regulated cell death pathway in schistosomes

Discovery and molecular characterization of a Bcl-2–regulated cell death pathway in schistosomes

Bim Upregulation by Histone Deacetylase Inhibitors Mediates Interactions with the Bcl-2 Antagonist ABT-737: Evidence for Distinct Roles for Bcl-2, Bcl-xL, and Mcl-1

A combination of in silico and SAR studies to identify binding hot spots of Bcl-xL inhibitors

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Product

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Bim Upregulation by Histone Deacetylase Inhibitors Mediates Interactions with the Bcl-2 Antagonist ABT-737: Evidence for Distinct Roles for Bcl-2, Bcl-x_L, and Mcl-1