Dynamics of the SS Loop Regulates SARM1′s Catalysis

motif in the SS loop, thereby restricting His640 flipping and preventing NAD engagement. Notably, chemical tethering of adjacent cysteine residues within the SS loop similarly suppresses its conformational dynamics, resulting in potent inhibition of catalysis. The essential role of SS loop dynamics uncovered here offers new mechanistic insight and establishes a foundation for developing therapeutic strategies targeting SARM1.