Molecular Determinants of Bim(BH3) Peptide Binding to Pro-Survival Proteins

Delgado-Soler, Laura; Pinto, Marta; Tanaka-Gil, Kaori; Rubio-Martínez, Jaime

doi:10.1021/ci3001666

Cited by 34 publications

(37 citation statements)

References 49 publications

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“…21). The direct visualization of different complexes in live cells identified a BIM S -BAD BH3 mutant as a specific partner for BCL-X L but not BCL-W and MCL-1; this approach could be extended to other mutants such as the MCL-1-specific BIM S 2A (49).…”

Section: Advances In Determining the Specificity Of Interaction Betwementioning

confidence: 99%

“…Given that MCL-1 has emerged as a critical prosurvival factor in a number of malignancies and in drug resistance (17), there is an urgent need to identify MCL-1-specific BH3 mimetics (18,19). The development of small molecules capable of targeting all the main antiapoptotic BCL-2 proteins is also of clear therapeutic interest (8,(20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

BH3 Mimetics: Status of the Field and New Developments

Billard

2013

Molecular Cancer Therapeutics

198

192

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Targeting apoptosis is an attractive approach in cancer therapy. The BH3-only proteins of the BCL-2 family (having only the BCL-2 homology domain BH3) can trigger apoptosis by binding to the prosurvival members of this family and neutralizing their functional activity (sequestration of the proapoptotic Bcl-2 family members). The "BH3 mimetic" concept has prompted the development of small molecules capable of mimicking BH3-only proteins and thus inducing apoptosis. The prototype BH3 mimetic ABT-737 selectively targets the three prosurvival proteins BCL-X L , BCL-2, and BCL-W (but not MCL-1 or A1) and its oral derivative ABT-263 has proved promising in clinical trials. Some putative BH3 mimetics are also tested clinically while others are still being characterized. This article recapitulates the various known BH3 mimetics and presents the recent developments in the field. The latter include (i) the identification of molecular determinants responsible for the specific interactions between BH3 motifs and the binding grooves of prosurvival proteins and (ii) the characterization of new compounds and particularly BH3 mimetics that antagonize either selectively MCL-1 or BCL-2 or a broad range of prosurvival proteins. These data are critical advances toward the discovery of novel anticancer agents. Mol Cancer Ther; 12(9); 1691-700. Ó2013 AACR.

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Section: Advances In Determining the Specificity Of Interaction Betwementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

BH3 Mimetics: Status of the Field and New Developments

Billard

2013

Molecular Cancer Therapeutics

198

192

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“…[14] Identical Bim-BH3 peptidesw ere used in those two studies.N otably,o ther researchersh ave explored the determinants on Bim-BH3 for in- Figure 2. [16] Readers may wish to check those previous studies to understand how Bim-BH3 engages those targets differently. The startingp oint of the y axis is 2000 nm,which was set as the cutoff for definingd etectable binding.Error bars for FP and HTRFr esults are derived from three parallel measurements.…”

Section: Resultsmentioning

confidence: 99%

Experimental Characterization of the Binding Affinities between Proapoptotic BH3 Peptides and Antiapoptotic Bcl‐2 Proteins

Kong

Zhou

et al. 2018

ChemMedChem

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The Bcl-2 family proteins are key regulators of the intrinsic apoptotic pathway and are among the validated targets for developing anticancer drugs. Protein-protein interactions between the pro- and antiapoptotic members of this family determine mitochondrial outer-membrane permeabilization. Elucidating such protein-protein interactions in a quantitative way is helpful for network pharmacology studies on the Bcl-2 family, which, in turn, will provide valuable guidance for developing new anticancer therapies. In this study, the binding affinities of the BH3 peptides derived from eight proapoptotic BH3-only proteins (i.e., Bid, Bim, Puma, Noxa, Bad, Bmf, Bik, Hrk) against five well-studied antiapoptotic proteins (i.e., Bcl-x , Bcl-2, Mcl-1, Bcl-w, Bfl-1) in the Bcl-2 family have been measured. Three different types of binding assay (i.e., surface plasmon resonance, fluorescence polarization, and homogeneous time-resolved fluorescence) were employed for cross-validation. The results confirmed that each proapoptotic BH3 peptide exhibited a distinct binding profile against the five antiapoptotic proteins. The binding data obtained herein serve as a fresh update or correction to existing knowledge. It is expected that such binding data will be helpful for building more accurate mathematical network models for depicting the complex protein-protein interactions within the Bcl-2 family.

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“…Similar findings with respect to the binding determinants were found for other complex structures. 30 …”

Section: Discussionmentioning

confidence: 99%

Molecular Determinants of Binding to thePlasmodiumSubtilisin-like Protease 1

Withers‐Martinez¹,

Blackman²,

Morris

et al. 2013

J. Chem. Inf. Model.

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PfSUB1, a subtilisin-like protease of the human malaria parasite Plasmodium falciparum, is known to play important roles during the life cycle of the parasite and has emerged as a promising antimalarial drug target. In order to provide a detailed understanding of the origin of binding determinants of PfSUB1 substrates, we performed molecular dynamics simulations in combination with MM-GBSA free energy calculations using a homology model of PfSUB1 in complex with different substrate peptides. Key interactions, as well as residues that potentially make a major contribution to the binding free energy, are identified at the prime and nonprime side of the scissile bond and comprise peptide residues P4 to P2′. This finding stresses the requirement for peptide substrates to interact with both prime and nonprime side residues of the PfSUB1 binding site. Analyzing the energetic contributions of individual amino acids within the peptide-PfSUB1 complexes indicated that van der Waals interactions and the nonpolar part of solvation energy dictate the binding strength of the peptides and that the most favorable interactions are formed by peptide residues P4 and P1. Hot spot residues identified in PfSUB1 are dispersed over the entire binding site, but clustered areas of hot spots also exist and suggest that either the S4-S2 or the S1-S2′ binding site should be exploited in efforts to design small molecule inhibitors. The results are discussed with respect to which binding determinants are specific to PfSUB1 and, therefore, might allow binding selectivity to be obtained.

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Molecular Determinants of Bim(BH3) Peptide Binding to Pro-Survival Proteins

Cited by 34 publications

References 49 publications

BH3 Mimetics: Status of the Field and New Developments

BH3 Mimetics: Status of the Field and New Developments

Experimental Characterization of the Binding Affinities between Proapoptotic BH3 Peptides and Antiapoptotic Bcl‐2 Proteins

Molecular Determinants of Binding to thePlasmodiumSubtilisin-like Protease 1

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