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Showing 1–30 of 30 results
Advanced filters: Author: Loren D Walensky Clear advanced filters

  • Resistance mutations in BCL-2 reduce the clinical efficacy of venetoclax. DeAngelo et al. show stapled BAD BH3 peptides can retain and even enhance binding to these mutants, offering a structurally informed strategy to overcome this mechanism of cancer drug resistance.

    • Thomas M. DeAngelo
    • Utsarga Adhikary
    • Loren D. Walensky
    ResearchOpen Access
    Nature Communications
    Volume: 16, P: 1-15

  • PUMA is a BCL-2 family protein that transmits stress signals to promote apoptosis. Upon DNA damage, a unique binding determinant within PUMA triggers partial unfolding of BCL-XL, resulting in the release of sequestered p53 and commitment to p53-dependent cell death.

    • Loren D Walensky
    News & Views
    Nature Chemical Biology
    Volume: 9, P: 141-143

  • The ongoing emergence of highly pathogenic viruses that evade immune-based therapies or lack interventions mandates new approaches, especially for on-demand prophylaxis. Here the authors provide a stapled lipopeptide platform for the rapid development of viral fusion inhibitors to combat outbreaks.

    • Gregory H. Bird
    • J. J. Patten
    • Loren D. Walensky
    ResearchOpen Access
    Nature Communications
    Volume: 15, P: 1-15

  • A disulfide tethering screen identified a molecule that covalently interacts with pro-apoptotic BAX at C126, inhibiting its activation.

    • Matthew W. McHenry
    • Peiwen Shi
    • Loren D. Walensky
    Research
    Nature Chemical Biology
    Volume: 20, P: 1022-1032

  • Prew et al. uncovered a structural basis for human VLCAD deficiency that arises from point mutations within the enzyme’s membrane-binding region, which was shown to fold as a putative α-helical hairpin. Helix-breaking mutations selectively disrupt membrane interaction and thus homeostatic function.

    • Michelle S. Prew
    • Christina M. Camara
    • Loren D. Walensky
    ResearchOpen Access
    Nature Communications
    Volume: 13, P: 1-12

  • BAK is a proapoptotic BCL-2–family protein that resides in the mitochondrial outer membrane and transforms into a toxic oligomeric pore in response to overwhelming cellular stress. Biochemical and structural analyses of hydrocarbon-stapled signaling peptides in complex with BAK establish a direct mechanism for BAK activation.

    • Loren D. Walensky
    News & Views
    Nature Structural & Molecular Biology
    Volume: 20, P: 536-538

  • The pro-apoptotic BAX protein is a monomer under homeostatic conditions and, in response to stress, transforms into oligomers that induce apoptosis. Here, the authors characterize structural features of BAX that individually stabilize the monomer while collectively contributing to oligomerization.

    • Noah B. Bloch
    • Thomas E. Wales
    • Loren D. Walensky
    ResearchOpen Access
    Nature Communications
    Volume: 12, P: 1-12

  • Glucokinase activators are attractive therapeutics in diabetes, but their benefits can be offset by hypoglycemia, owing to the allosteric enhancement of the enzyme's glucose affinity. The biochemical and structural dissection of the interaction between glucokinase and a phosphomimetic of the BH3 α-helix derived from human BAD, a glucokinase-binding partner, demonstrates a new binding region and distinct mode of enzyme activation.

    • Benjamin Szlyk
    • Craig R Braun
    • Nika N Danial
    Research
    Nature Structural & Molecular Biology
    Volume: 21, P: 36-42

  • MCL-1 has emerged as a major oncogenic and chemoresistance factor. A screen of stapled peptide helices identified the MCL-1 BH3 domain as selectively inhibiting MCL-1 among the related anti-apoptotic Bcl-2 family members, providing insights into the molecular determinants of binding specificity and a new approach for sensitizing cancer cells to apoptosis.

    • Michelle L Stewart
    • Emiko Fire
    • Loren D Walensky
    Research
    Nature Chemical Biology
    Volume: 6, P: 595-601

  • Disulfide-bond formation between a cysteine pair at the groove and C-terminal α-helix of the anti-apoptotic protein BFL-1 operates as a redox switch that controls the accessibility of the protein’s anti-apoptotic pocket, which is important for the regulation of pro-apoptotic BCL-2 family members.

    • Kyle J. Korshavn
    • Thomas E. Wales
    • Loren D. Walensky
    Research
    Nature Structural & Molecular Biology
    Volume: 27, P: 781-789

  • A structural analysis of the apoptosis-inducing protein BAX in complex with a peptide derived from its activator BIM reveals an unforeseen interaction site that does not involve the classic hydrophobic groove reported for inhibitors of apoptosis. This identification of BAX's activation site provides mechanistic insights into a cell's demise.

    • Evripidis Gavathiotis
    • Motoshi Suzuki
    • Loren D. Walensky
    Research
    Nature
    Volume: 455, P: 1076-1081

  • EZH2 and EED are components of the Polycomb repressive complex 2 (PRC2), a ‘writer’ complex involved in histone methylation. A stapled peptide that disrupts the EZH2-EED interaction arrests growth in PRC2-dependent leukemia cells and offers an alternative mode for EZH2 inhibition.

    • Woojin Kim
    • Gregory H Bird
    • Stuart H Orkin
    Research
    Nature Chemical Biology
    Volume: 9, P: 643-650

  • Identification of an allosteric mechanism disrupting the antiapoptotic BH3 binding activity of MCL-1 offers a new approach for targeting the apoptotic resistance of human cancers.

    • Susan Lee
    • Thomas E Wales
    • Loren D Walensky
    Research
    Nature Structural & Molecular Biology
    Volume: 23, P: 600-607

  • An NMR fragment screen identified a small molecule that binds to an allosteric site on the proapoptotic protein BAX and synergizes with the BIM BH3 domain to conformationally activate BAX and enhance BAX-mediated membrane poration.

    • Jonathan R Pritz
    • Franziska Wachter
    • Loren D Walensky
    Research
    Nature Chemical Biology
    Volume: 13, P: 961-967

  • Detailed biophysical, microscopy, and statistical analyses of hydrocarbon-stapled peptide variants revealed how a combination of critical parameters such as hydrophobicity, α-helicity and isoelectric point influence cellular permeability.

    • Gregory H Bird
    • Emanuele Mazzola
    • Loren D Walensky
    Research
    Nature Chemical Biology
    Volume: 12, P: 845-852

  • A computational screen identifies a small-molecule activator of proapoptotic BAX that selectively binds to the BAX trigger site, inducing characteristic conformational changes, oligomerization and BAX-dependent cell death.

    • Evripidis Gavathiotis
    • Denis E Reyna
    • Loren D Walensky
    Research
    Nature Chemical Biology
    Volume: 8, P: 639-645

  • β-cell dysfunction in diabetes is caused by glucose and inflammation toxicity. Here, Fu et al. show that β-cell glucose metabolism can be protective though pyruvate carboxylase–mediated shunting of arginine to ureagenesis and away from toxic nitric oxide production, thus suppressing inflammation.

    • Accalia Fu
    • Juan Carlos Alvarez-Perez
    • Nika N. Danial
    Research
    Nature Metabolism
    Volume: 2, P: 432-446

  • This Review highlights recent structure–function insights that inform diverse pharmacologic strategies for direct targeting of BAX to alternatively reactivate or inhibit apoptosis in diseases of pathologic cell survival or premature cellular demise.

    • Loren D. Walensky
    Reviews
    Nature Chemical Biology
    Volume: 15, P: 657-665

  • The authors identify EZH2 as a general underlying dependency of tumors with mutations in the SWI/SNF chromatin regulator complex, and they show that EZH2's pro-tumorigenic role may be dependent on non-catalytic activities. This may pose new opportunities and challenges for using EZH2 as a cancer therapy target.

    • Kimberly H Kim
    • Woojin Kim
    • Charles W M Roberts
    Research
    Nature Medicine
    Volume: 21, P: 1491-1496