ArticleeLife2020
Structural basis for SARM1 inhibition and activation under energetic stress.
Article in eLife, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 78 papers.
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Who cites it
78 citing papers in PubMed, 121 citations in OpenAlex.
- Direct activation of SARM1 by dsDNA is not supported by biochemical and cellular evidence.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- The insect effector CSPs activate an atypical plant TNL immune receptor.Plant cell reports · 2026Article
- Article
- Review
- Peripheral Neuropathy in Metabolic Stress.International journal of molecular sciences · 2026Review
- Review
- Boldine inhibits SARM1 NADase Activity and Preserves Axonal Integrity After Nerve Injury.bioRxiv : the preprint server for biology · 2026Article
- The rise and fall of SARM1 base-exchange inhibitors.Communications chemistry · 2026Article
- SARM1 activation promotes axonal degeneration via a two-step phase transition.Nature chemical biology · 2026Article
- Therapeutic safety implications of SARM1 active site inhibitors: subinhibitory concentrations cause neurodegeneration.npj drug discovery · 2025Article
- SARM1: The Checkpoint of Axonal Degeneration in the Nervous System Disorders.Molecular neurobiology · 2025Review
- Suppressing phagocyte activation by overexpressing the phosphatidylserine lipase ABHD12 preserves sarmopathic nerves.iScience · 2025Article
- The role of NADnpj metabolic health and disease · 2025Review
- Optimization of Brain Penetrant SARM1 Orthosteric Inhibitors and Discovery of Their Paradoxical Subinhibitory Activation.ACS medicinal chemistry letters · 2025Article
- Evolutionarily ancient functions of enzymatic TIR proteins in innate immunity.Trends in immunology · 2025Review
- Stepwise activation of SARM1 for cell death and axon degeneration revealed by a biosynthetic NMN mimic.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Emerging interactions between mitochondria and NADTrends in endocrinology and metabolism: TEM · 2025Review
- Programmed neurite degeneration in human central nervous system neurons driven by changes in NADCell death & disease · 2025Article
- Gap junction intercellular communications regulates activation of SARM1 and protects against axonal degeneration.Cell death & disease · 2025Article
- Review
18 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
11 authors at 7 institutions in 4 countries.
Funding
Abstract
SARM1, an executor of axonal degeneration, displays NADase activity that depletes the key cellular metabolite, NAD+, in response to nerve injury. The basis of SARM1 inhibition and its activation under stress conditions are still unknown. Here, we present cryo-EM maps of SARM1 at 2.9 and 2.7 Å resolutions. These indicate that SARM1 homo-octamer avoids premature activation by assuming a packed conformation, with ordered inner and peripheral rings, that prevents dimerization and activation of the catalytic domains. This inactive conformation is stabilized by binding of SARM1's own substrate NAD+ in an allosteric location, away from the catalytic sites. This model was validated by mutagenesis of the allosteric site, which led to constitutively active SARM1. We propose that the reduction of cellular NAD+ concentration contributes to the disassembly of SARM1's peripheral ring, which allows formation of active NADase domain dimers, thereby further depleting NAD+ to cause an energetic catastrophe and cell death.
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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.