ArticleNature chemical biology2024
Global signal peptide profiling reveals principles of selective Sec61 inhibition.
Article in Nature chemical biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
What it found
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The trial behind it
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Who cites it
6 citing papers in PubMed, 8 citations in OpenAlex.
- Halting translation by the letter with sequence-selective small molecules.Nature chemical biology · 2026Review
- Pairwise transmembrane domain insertion during multipass protein biogenesis.Molecular cell · 2026Article
- A delayed translocation into the endoplasmic reticulum controls the post-translational modifications of PD-L1.Nature communications · 2026Article
- Engineering mammalian protein secretion: Toward the convergence of high-throughput biology and computational methods.Cell systems · 2025Review
- A light-resuming strategy as a screening method for selecting Sec61 inhibitors down-modulating PD-L1 expression.Nature communications · 2025Article
- Toward Understanding the Mechanism of Client-Selective Small Molecule Inhibitors of the Sec61 Translocon.Journal of molecular recognition : JMR · 2025Review
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cotransins target the Sec61 translocon and inhibit the biogenesis of an undefined subset of secretory and membrane proteins. Remarkably, cotransin inhibition depends on the unique signal peptide (SP) of each Sec61 client, which is required for cotranslational translocation into the endoplasmic reticulum. It remains unknown how an SP's amino acid sequence and biophysical properties confer sensitivity to structurally distinct cotransins. Here we describe a fluorescence-based, pooled-cell screening platform to interrogate nearly all human SPs in parallel. We profiled two cotransins with distinct effects on cancer cells and discovered a small subset of SPs, including the oncoprotein human epidermal growth factor receptor 3 (HER3), with increased sensitivity to the more selective cotransin, KZR-9873. By comparing divergent mouse and human orthologs, we unveiled a position-dependent effect of arginine on SP sensitivity. Our multiplexed profiling platform reveals how cotransins can exploit subtle sequence differences to achieve SP discrimination.
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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.