Article Synopsis
- The SARM1 protein is crucial for axon degeneration and is a potential target for treating neurodegenerative diseases.
- A new SARM1 inhibitor, 1AD, was developed by exchanging parts of the molecule with NAD, which is essential for SARM1's function.
- The study uncovered the structural changes in SARM1 during activation, showing how it binds to substrates and suggesting ways to create new drugs that inhibit SARM1's damaging effects.
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Article Abstract
The NADase SARM1 (sterile alpha and TIR motif containing 1) is a key executioner of axon degeneration and a therapeutic target for several neurodegenerative conditions. We show that a potent SARM1 inhibitor undergoes base exchange with the nicotinamide moiety of nicotinamide adenine dinucleotide (NAD) to produce the bona fide inhibitor 1AD. We report structures of SARM1 in complex with 1AD, NAD mimetics and the allosteric activator nicotinamide mononucleotide (NMN). NMN binding triggers reorientation of the armadillo repeat (ARM) domains, which disrupts ARM:TIR interactions and leads to formation of a two-stranded TIR domain assembly. The active site spans two molecules in these assemblies, explaining the requirement of TIR domain self-association for NADase activity and axon degeneration. Our results reveal the mechanisms of SARM1 activation and substrate binding, providing rational avenues for the design of new therapeutics targeting SARM1.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9188649 | PMC |
| http://dx.doi.org/10.1016/j.molcel.2022.03.007 | DOI Listing |
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