ArticleNature2017
Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40.
Article in Nature, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 331 papers.
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Who cites it
331 citing papers in PubMed, 527 citations in OpenAlex.
- Synergistic role of TFEB/TFE3 and mTORC1 in kidney cystogenesis and tumorigenesis.Cell death and differentiation · 2026Article
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- Renal cell carcinoma: molecular understanding and therapeutic development.Cell death and differentiation · 2026Review
- Dietary protein governs the role of insulin signaling in the postprandial regulation of hepatic mTORC1.Nature communications · 2026Article
- SIRT1 Exon 2-Encoded IDR Gates CREB-Dependent Transcriptional Timing During Fasting.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Small-molecule cocktail 2SM promotes heart regeneration via inducing embryonic-like cardiomyocyte state.Cell regeneration (London, England) · 2026Article
- Structural mechanism of TOPBP1 activating the ATR-ATRIP replication checkpoint kinase.Nature structural & molecular biology · 2026Article
- The Nucleolus in Human Disease: Ribosome Biogenesis, Nucleolar Surveillance, and Therapeutic Opportunities.Biomolecules · 2026Review
- A Function-Centric Framework for Mitochondrial Quality Control.Biomolecules · 2026Review
- Global cellular responses to lysosomal damage.Current biology : CB · 2026Review
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- Geospatial genetic evolution and phenotypic plasticity in triple-negative breast cancer.Genome medicine · 2026Article
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- Drug resistant epilepsy driven byEpilepsy & behavior reports · 2026Article
- METTL1-mediated mOncogene · 2026Article
- Targeting the GSK-3β/mTOR axis: a novel pharmacological strategy for preeclampsia prevention and treatment.Naunyn-Schmiedeberg's archives of pharmacology · 2026Review
- A TerminaTOR of mTORC1 signaling.Nature chemical biology · 2026Article
- Genetically targeted mTORC1 inhibitor reveals transcriptional control by nuclear mTORC1.Nature chemical biology · 2026Article
- DH_27, a right-half derivative of renieramycin T, induce apoptosis through inhibition of mTOR signaling for lung cancer suppression.Scientific reports · 2026Article
- PRAS40 activates the IRE1α-XBP-1-mediated unfolded protein response to exacerbate colorectal cancer by enhancing ST6Gal1-dependent α-2, 6 sialylation of GRP78.Neoplasia (New York, N.Y.) · 2026Article
271 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
The mechanistic target of rapamycin complex 1 (mTORC1) controls cell growth and metabolism in response to nutrients, energy levels, and growth factors. It contains the atypical kinase mTOR and the RAPTOR subunit that binds to the Tor signalling sequence (TOS) motif of substrates and regulators. mTORC1 is activated by the small GTPase RHEB (Ras homologue enriched in brain) and inhibited by PRAS40. Here we present the 3.0 ångström cryo-electron microscopy structure of mTORC1 and the 3.4 ångström structure of activated RHEB-mTORC1. RHEB binds to mTOR distally from the kinase active site, yet causes a global conformational change that allosterically realigns active-site residues, accelerating catalysis. Cancer-associated hyperactivating mutations map to structural elements that maintain the inactive state, and we provide biochemical evidence that they mimic RHEB relieving auto-inhibition. We also present crystal structures of RAPTOR-TOS motif complexes that define the determinants of TOS recognition, of an mTOR FKBP12-rapamycin-binding (FRB) domain-substrate complex that establishes a second substrate-recruitment mechanism, and of a truncated mTOR-PRAS40 complex that reveals PRAS40 inhibits both substrate-recruitment sites. These findings help explain how mTORC1 selects its substrates, how its kinase activity is controlled, and how it is activated by cancer-associated mutations.
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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.