ArticleeLife2021
Cryo-EM reconstructions of inhibitor-bound SMG1 kinase reveal an autoinhibitory state dependent on SMG8.
Article in eLife, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 32 citations in OpenAlex.
- A targetable dependency on nonsense-mediated decay for cellular homeostasis and immune control in small cell lung cancer.Molecular cancer · 2026Article
- Article
- SMG1:SMG8:SMG9-complex integrity supports efficient execution of nonsense-mediated mRNA decay.Nucleic acids research · 2026Article
- Pharmacological perturbation of splicing elicits SMG1 reduction: Implications for cancer therapy.iScience · 2026Article
- Functional phosphoproteomic analysis of SMG1 in nonsense-mediated mRNA decay and DNA damage repair in cancer.Frontiers in systems biology · 2026Article
- An alternative cytoplasmic SFPQ isoform with reduced phase separation potential is up-regulated in ALS.Science advances · 2025Article
- Article
- Identification of nonsense-mediated decay inhibitors that alter the tumor immune landscape.eLife · 2025Article
- Messenger RNA Surveillance: Current Understanding, Regulatory Mechanisms, and Future Implications.Molecular biotechnology · 2025Review
- mTORC1, the maestro of cell metabolism and growth.Genes & development · 2025Review
- UPF1 helicase orchestrates mutually exclusive interactions with the SMG6 endonuclease and UPF2.Nucleic acids research · 2024Article
- PinMyMetal: A hybrid learning system to accurately model metal binding sites in macromolecules.Research square · 2024Article
- Translation-coupled mRNA quality control mechanisms.The EMBO journal · 2023Review
- Inhibition of nonsense-mediated mRNA decay reduces the tumorigenicity of human fibrosarcoma cells.NAR cancer · 2023Article
- HNRNPH1 regulates the neuroprotective cold-shock protein RBM3 expression through poison exon exclusion.The EMBO journal · 2023Article
- Participation of ATM, SMG1, and DDX5 in a DNA Damage-Induced Alternative Splicing Pathway.Radiation research · 2023Article
- A conditionalScience advances · 2023Article
- SMG8/SMG9 Heterodimer Loss Modulates SMG1 Kinase to Drive ATR Inhibitor Resistance.Cancer research · 2022Article
- Structure and regulation of the nuclear exosome targeting complex guides RNA substrates to the exosome.Molecular cell · 2022Article
- No-nonsense: insights into the functional interplay of nonsense-mediated mRNA decay factors.The Biochemical journal · 2022Review
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The PI3K-related kinase (PIKK) SMG1 monitors the progression of metazoan nonsense-mediated mRNA decay (NMD) by phosphorylating the RNA helicase UPF1. Previous work has shown that the activity of SMG1 is impaired by small molecule inhibitors, is reduced by the SMG1 interactors SMG8 and SMG9, and is downregulated by the so-called SMG1 insertion domain. However, the molecular basis for this complex regulatory network has remained elusive. Here, we present cryo-electron microscopy reconstructions of human SMG1-9 and SMG1-8-9 complexes bound to either a SMG1 inhibitor or a non-hydrolyzable ATP analog at overall resolutions ranging from 2.8 to 3.6 Å. These structures reveal the basis with which a small molecule inhibitor preferentially targets SMG1 over other PIKKs. By comparison with our previously reported substrate-bound structure (Langer et al.,2020), we show that the SMG1 insertion domain can exert an autoinhibitory function by directly blocking the substrate-binding path as well as overall access to the SMG1 kinase active site. Together with biochemical analysis, our data indicate that SMG1 autoinhibition is stabilized by the presence of SMG8. Our results explain the specific inhibition of SMG1 by an ATP-competitive small molecule, provide insights into regulation of its kinase activity within the NMD pathway, and expand the understanding of PIKK regulatory mechanisms in general.
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