ArticleeLife2017
Epistatic mutations in PUMA BH3 drive an alternate binding mode to potently and selectively inhibit anti-apoptotic Bfl-1.
Article in eLife, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
24 citing papers in PubMed, 44 citations in OpenAlex.
- Understanding the Functional Dependence and Inhibition of the Bcl‑2 Pro-Survival Proteins in a Wide Spectrum of Cancers toward Precision Medicine.ACS pharmacology & translational science · 2025Article
- Targeted Penetrating Motif Engineering of BH3 Mimetic: Harnessing Non-Canonical Amino Acids for Coinhibition of MCL-1 and BCL-xL in Acute Myeloid Leukemia.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Apoptotic Potential of Iloneoside from Gongronema latifolium Benth against Prostate Cancer Cells Using In Vitro and In Silico Approach.Cell biochemistry and biophysics · 2025Article
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- Rapid Evaluation of Staple Placement in Stabilized α Helices Using Bacterial Surface Display.ACS chemical biology · 2023Article
- Peptides from human BNIP5 and PXT1 and non-native binders of pro-apoptotic BAK can directly activate or inhibit BAK-mediated membrane permeabilization.Structure (London, England : 1993) · 2023Article
- Target Prediction of 5,10,15,20-Tetrakis(4'-Sulfonatophenyl)-Porphyrin Using Molecular Docking.Pharmaceutics · 2022Article
- Design of Protein Segments and Peptides for Binding to Protein Targets.Biodesign research · 2022Review
- Uncovering the basis of protein-protein interaction specificity with a combinatorially complete library.eLife · 2020Article
- PI3Kδ inhibition reshapes follicular lymphoma-immune microenvironment cross talk and unleashes the activity of venetoclax.Blood advances · 2020Article
- N-locking stabilization of covalent helical peptides: Application to Bfl-1 antagonists.Chemical biology & drug design · 2020Article
- Alterations of the interactome of Bcl-2 proteins in breast cancer at the transcriptional, mutational and structural level.PLoS computational biology · 2019Article
- Advances in protein structure prediction and design.Nature reviews. Molecular cell biology · 2019Review
- Molecular evolution of peptides by yeast surface display technology.MedChemComm · 2019Review
- Prediction of venetoclax activity in precursor B-ALL by functional assessment of apoptosis signaling.Cell death & disease · 2019Article
- Tertiary Structural Motif Sequence Statistics Enable Facile Prediction and Design of Peptides that Bind Anti-apoptotic Bfl-1 and Mcl-1.Structure (London, England : 1993) · 2019Article
- Data-driven supervised learning of a viral protease specificity landscape from deep sequencing and molecular simulations.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Peptide design by optimization on a data-parameterized protein interaction landscape.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Splicing modulation sensitizes chronic lymphocytic leukemia cells to venetoclax by remodeling mitochondrial apoptotic dependencies.JCI insight · 2018Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Overexpression of anti-apoptotic Bcl-2 family proteins contributes to cancer progression and confers resistance to chemotherapy. Small molecules that target Bcl-2 are used in the clinic to treat leukemia, but tight and selective inhibitors are not available for Bcl-2 paralog Bfl-1. Guided by computational analysis, we designed variants of the native BH3 motif PUMA that are > 150-fold selective for Bfl-1 binding. The designed peptides potently trigger disruption of the mitochondrial outer membrane in cells dependent on Bfl-1, but not in cells dependent on other anti-apoptotic homologs. High-resolution crystal structures show that designed peptide FS2 binds Bfl-1 in a shifted geometry, relative to PUMA and other binding partners, due to a set of epistatic mutations. FS2 modified with an electrophile reacts with a cysteine near the peptide-binding groove to augment specificity. Designed Bfl-1 binders provide reagents for cellular profiling and leads for developing enhanced and cell-permeable peptide or small-molecule inhibitors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.