7m6k

Crystal structure of the ARM domain from Drosophila SARM1 in complex with VMN

spinqualitylabelsall models 7m6k, resolution 1.69Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.69Å Ligands: NA, YRJ Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Axon loss underlies symptom onset and progression in many neurodegenerative disorders. Axon degeneration in injury and disease is promoted by activation of the NAD-consuming enzyme SARM1. Here, we report a novel activator of SARM1, a metabolite of the pesticide and neurotoxin vacor. Removal of SARM1 completely rescues mouse neurons from vacor-induced neuron and axon death in vitro and in vivo. We present the crystal structure of the Drosophila SARM1 regulatory domain complexed with this activator, the vacor metabolite VMN, which as the most potent activator yet known is likely to support drug development for human SARM1 and NMNAT2 disorders. This study indicates the mechanism of neurotoxicity and pesticide action by vacor, raises important questions about other pyridines in wider use today, provides important new tools for drug discovery, and demonstrates that removing SARM1 can robustly block programmed axon death induced by toxicity as well as genetic mutation. Neurotoxin-mediated potent activation of the axon degeneration regulator SARM1.,Loreto A, Angeletti C, Gu W, Osborne A, Nieuwenhuis B, Gilley J, Merlini E, Arthur-Farraj P, Amici A, Luo Z, Hartley-Tassell L, Ve T, Desrochers LM, Wang Q, Kobe B, Orsomando G, Coleman MP Elife. 2021 Dec 6;10. pii: 72823. doi: 10.7554/eLife.72823. PMID:34870595 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also SARM1 3D structures

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