The NADase SARM1 (sterile alpha and TIR motif containing 1) is a key executioner of axon degeneration and there is great interest in developing SARM1 enzyme inhibitors as candidate therapies for multiple neurodegenerative diseases.
Through a combined approach of X-ray crystallography and cryo-EM we uncovered the molecular mechanism of SARM1 inhibition by a compound (DSRM-3716), demonstrating that it undergoes a base-exchange reaction with the nicotinamide moiety of NAD+, and that the transferase product is the bona fide inhibitor. Further more we reveal the activated state of SARM1 for the first time.