Unveiling New Binding Sites and Allosteric Regulation Mechanisms of LSD1 for Novel Therapeutics

Lysine-specific demethylase 1 (LSD1) regulates key cellular
processes
through both demethylase-dependent and -independent functions. Current
clinical LSD1 inhibitors target its demethylase functions, and issues
like the inability to fully modulate LSD1’s demethylase-independent
functions have limited their clinical efficacy. SP2509, an allosteric
LSD1 inhibitor, can affect both demethylase-dependent and -independent
functions of LSD1. Understanding the allosteric regulation mechanisms
of SP2509 may facilitate the development of new LSD1 inhibitors. Using
SP2509 as a probe, two new binding modes are identified in this work,
both of which can alter the conformation of substrate binding pocket,
effectively blocking H3 substrate binding and inhibiting the demethylase
activity. Interestingly, one binding mode induces significant allosteric
bending of Tower/CoREST domain, disrupting the nucleosome substrate
bindingan effect not previously reported. This unique binding
mode is also validated through in vitro biochemical
characterizations. These findings provide invaluable structural insights
for designing next-generation LSD1 inhibitors for novel therapeutics.