ArticleNature structural & molecular biology2016
Allosteric inhibition of antiapoptotic MCL-1.
Article in Nature structural & molecular biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 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.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
23 citing papers in PubMed, 58 citations in OpenAlex.
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- Protein structural dynamics in covalent drug design: insights from irreversible and reversible covalent inhibitors.RSC chemical biology · 2026Review
- VDAC2 and Bak scarcity in liver mitochondria enables targeting hepatocarcinoma while sparing hepatocytes.Nature communications · 2025Article
- Recent advances in targeting the "undruggable" proteins: from drug discovery to clinical trials.Signal transduction and targeted therapy · 2023Review
- Innate Conformational Dynamics Drive Binding Specificity in Anti-Apoptotic Proteins Mcl-1 and Bcl-2.Biochemistry · 2023Article
- Targeting MCL-1 protein to treat cancer: opportunities and challenges.Frontiers in oncology · 2023Review
- Scaffold hopping from indoles to indazoles yields dual MCL-1/BCL-2 inhibitors from MCL-1 selective leads.RSC medicinal chemistry · 2022Article
- Recent applications of covalent chemistries in protein-protein interaction inhibitors.RSC medicinal chemistry · 2022Review
- Myeloid cell leukemia-1: a formidable barrier to anticancer therapeutics and the quest of targeting it.Exploration of targeted anti-tumor therapy · 2022Review
- Visualizing and trapping transient oligomers in amyloid assembly pathways.Biophysical chemistry · 2021Review
- Modulation of Amyloidogenic Protein Self-Assembly Using Tethered Small Molecules.Journal of the American Chemical Society · 2020Article
- A redox switch regulates the structure and function of anti-apoptotic BFL-1.Nature structural & molecular biology · 2020Article
- Homogeneous Oligomers of Pro-apoptotic BAX Reveal Structural Determinants of Mitochondrial Membrane Permeabilization.Molecular cell · 2020Article
- Identification of a Covalent Molecular Inhibitor of Anti-apoptotic BFL-1 by Disulfide Tethering.Cell chemical biology · 2020Article
- Inhibition of Anti-Apoptotic Bcl-2 Proteins in Preclinical and Clinical Studies: Current Overview in Cancer.Cells · 2020Review
- Site-Dependent Cysteine Lipidation Potentiates the Activation of Proapoptotic BAX.Cell reports · 2020Article
- Photocatalytic proximity labelling of MCL-1 by a BH3 ligand.Communications chemistry · 2019Article
- Recommendations for performing, interpreting and reporting hydrogen deuterium exchange mass spectrometry (HDX-MS) experiments.Nature methods · 2019Review
- Small-molecule allosteric inhibitors of BAX.Nature chemical biology · 2019Article
- Allosteric sensitization of proapoptotic BAX.Nature chemical biology · 2017Article
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
MCL-1 is an antiapoptotic BCL-2 family protein that has emerged as a major pathogenic factor in human cancer. Like BCL-2, MCL-1 bears a surface groove whose function is to sequester the BH3 killer domains of proapoptotic BCL-2 family members, a mechanism harnessed by cancer cells to establish formidable apoptotic blockades. Although drugging the BH3-binding groove has been achieved for BCL-2, translating this approach to MCL-1 has been challenging. Here, we report an alternative mechanism for MCL-1 inhibition by small-molecule covalent modification of C286 at a new interaction site distant from the BH3-binding groove. Our structure-function analyses revealed that the BH3 binding capacity of MCL-1 and its suppression of BAX are impaired by molecular engagement, a phenomenon recapitulated by C286W mutagenic mimicry in vitro and in mouse cells. Thus, we characterize an allosteric mechanism for disrupting the antiapoptotic BH3 binding activity of MCL-1, informing a new strategy for disarming MCL-1 in cancer.
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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.