7M6K

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

Summary for 7M6K

• Entry DOI: 10.2210/pdb7m6k/pdb
• Descriptor: Isoform B of NAD(+) hydrolase sarm1, 3-({[(4-nitrophenyl)carbamoyl]amino}methyl)-1-(5-O-phosphono-beta-D-ribofuranosyl)pyridin-1-ium, SODIUM ION, ... (4 entities in total)
• Functional Keywords: neurotoxicity, axon degeneration, nadase, arm domain, immune system
• Biological source: Drosophila melanogaster (Fruit fly)
• Total number of polymer chains: 2
• Total formula weight: 69817.52

Authors

Gu, W.,Luo, Z.,Kobe, B. (deposition date: 2021-03-25, release date: 2022-02-02, Last modification date: 2024-10-16)

Primary citation

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, L.M.,Wang, Q.,Kobe, B.,Orsomando, G.,Coleman, M.P.
Neurotoxin-mediated potent activation of the axon degeneration regulator SARM1.
Elife, 10:-, 2021

PubMed Abstract: 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 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.

PubMed: 34870595
DOI: 10.7554/eLife.72823

Experimental method

X-RAY DIFFRACTION (1.69 Å)