| First Author | Shi Y | Year | 2022 |
| Journal | Mol Cell | Volume | 82 |
| Issue | 9 | Pages | 1643-1659.e10 |
| PubMed ID | 35334231 | Mgi Jnum | J:352986 |
| Mgi Id | MGI:7286125 | Doi | 10.1016/j.molcel.2022.03.007 |
| Citation | Shi Y, et al. (2022) Structural basis of SARM1 activation, substrate recognition, and inhibition by small molecules. Mol Cell 82(9):1643-1659.e10 |
| abstractText | 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. |
