ArticleNature chemical biology2023
Signal peptide mimicry primes Sec61 for client-selective inhibition.
Article in Nature chemical biology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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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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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
19 citing papers in PubMed, 33 citations in OpenAlex.
- A mycobacterial Sec61 inhibitor disrupts lysosome function by blocking Vacuolar-ATPase biosynthesis.European journal of cell biology · 2026Article
- Topogenic sequence recognition at TIM complexes revealed by a stendomycin-bound structure.Nature chemical biology · 2026Article
- Pairwise transmembrane domain insertion during multipass protein biogenesis.Molecular cell · 2026Article
- Macrocyclic Molecular Glues for the 14-3-3/ChREBP Interaction: Affinity and Cooperativity in an Inverse Relationship.Angewandte Chemie (International ed. in English) · 2026Article
- SEC61: a potential therapeutic target in transplantation.Frontiers in immunology · 2026Review
- A light-resuming strategy as a screening method for selecting Sec61 inhibitors down-modulating PD-L1 expression.Nature communications · 2025Article
- Lipid Scrambling Pathways in the Sec61 Translocon Complex.Journal of the American Chemical Society · 2025Article
- Cotranslational membrane insertion of the voltage-sensitive KProceedings of the National Academy of Sciences of the United States of America · 2025Article
- Toward Understanding the Mechanism of Client-Selective Small Molecule Inhibitors of the Sec61 Translocon.Journal of molecular recognition : JMR · 2025Review
- Global signal peptide profiling reveals principles of selective Sec61 inhibition.Nature chemical biology · 2024Article
- A unifying model for membrane protein biogenesis.Nature structural & molecular biology · 2024Review
- Article
- Diastereomers of Coibamide A Show Altered Sec61 Client Selectivity and Ligand-Dependent Activity against Patient-Derived Glioma Stem-like Cells.ACS pharmacology & translational science · 2024Article
- Linear motifs regulating protein secretion, sorting and autophagy in Leishmania parasites are diverged with respect to their host equivalents.PLoS computational biology · 2024Article
- Molecular view of ER membrane remodeling by the Sec61/TRAP translocon.EMBO reports · 2023Article
- A common mechanism of Sec61 translocon inhibition by small molecules.Nature chemical biology · 2023Article
- Article
- Review
- Editorial: The evolving picture of CaFrontiers in physiology · 2023Article
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Authors and funding
21 authors at 3 institutions in 3 countries.
Funding
Abstract
Preventing the biogenesis of disease-relevant proteins is an attractive therapeutic strategy, but attempts to target essential protein biogenesis factors have been hampered by excessive toxicity. Here we describe KZR-8445, a cyclic depsipeptide that targets the Sec61 translocon and selectively disrupts secretory and membrane protein biogenesis in a signal peptide-dependent manner. KZR-8445 potently inhibits the secretion of pro-inflammatory cytokines in primary immune cells and is highly efficacious in a mouse model of rheumatoid arthritis. A cryogenic electron microscopy structure reveals that KZR-8445 occupies the fully opened Se61 lateral gate and blocks access to the lumenal plug domain. KZR-8445 binding stabilizes the lateral gate helices in a manner that traps select signal peptides in the Sec61 channel and prevents their movement into the lipid bilayer. Our results establish a framework for the structure-guided discovery of novel therapeutics that selectively modulate Sec61-mediated protein biogenesis.
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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.