ArticleScience (New York, N.Y.)2025
Structural basis for LZTR1 recognition of RAS GTPases for degradation.
Article in Science (New York, N.Y.), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Multifaceted roles of KCTD17 in cellular homeostasis and disease.BMB reports · 2026Review
- Drug repurposing in KRAS G12C-mutant NSCLC: a focus on resistance mechanisms and clinical strategies.Naunyn-Schmiedeberg's archives of pharmacology · 2026Review
- The recognition of RAS proteins by LZTR1 shares a conserved mechanism among the GTPase superfamily.Science China. Life sciences · 2026Article
- Article
- Evolution of KRAS molecular glues: from allele-selective to Pan-RAS and protein-protein interaction modulators.Acta pharmacologica Sinica · 2026Review
- Neddylation-dependent CUL3-KLHL12 E3 ligase drives microglial oxidative stress and neuroinflammation in traumatic brain injury by targeting GCLM for degradation.Journal of translational medicine · 2026Article
- A renaissance in targeting the PI3K/AKT/mTOR pathway.Nature reviews. Drug discovery · 2026Review
- Mechanistic insights on spatiotemporal control of Ras-signaling.Biological chemistry · 2026Review
- A Novel Paradigm for Targeting Challenging Targets: Advancing Technologies and Future Directions of Molecular Glue Degraders.Molecules (Basel, Switzerland) · 2026Review
- Phosphorylation Protects Oncogenic RAS from LZTR1-Mediated Degradation.bioRxiv : the preprint server for biology · 2026Article
- Intrinsic resistance to RAS inhibitors is driven by dysregulation of KRAS degradation.Nature communications · 2025Article
Corrections and comments
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Authors and funding
12 authors.
Funding
Abstract
The RAS family of small guanosine triphosphatases (GTPases) are tightly regulated signaling molecules that are further modulated by ubiquitination and proteolysis. Leucine Zipper-like Transcription Regulator 1 (LZTR1), a substrate adapter of the Cullin-3 RING E3 ubiquitin ligase, binds specific RAS GTPases and promotes their ubiquitination and proteasomal degradation. We present structures of LZTR1 Kelch domains bound to RIT1, MRAS, and KRAS, revealing interfaces that govern RAS isoform selectivity and nucleotide specificity. Biochemical and structural analyses of disease-associated Kelch domain mutations revealed three types of alterations: impaired substrate interaction, loop destabilization, and blade-blade repulsion. In cellular and mouse models, mutations disrupting substrate binding phenocopied LZTR1 loss, underscoring its substrate specificity. These findings define RAS recognition mechanisms by LZTR1 and suggest a molecular glue strategy to degrade oncogenic KRAS.
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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 Socratic graph.