Unveiling New Binding Sites and Allosteric Regulation Mechanisms of LSD1 for Novel Therapeutics DOI
Kecheng Yang, Jinbo Xiong,

Yuting Shi

и другие.

Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Май 16, 2025

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

Язык: Английский

Mechanism of lncRNA gadd7 regulating mitofusin 1 expression by recruiting LSD1 to down-regulate H3K9me3 level, and mediating mitophagy in alveolar type II epithelial cell apoptosis in hyperoxia-induced acute lung injury DOI Creative Commons
Guoyue Liu,

Guiyang Jia,

Yingcong Ren

и другие.

Cell Biology and Toxicology, Год журнала: 2025, Номер 41(1)

Опубликована: Апрель 29, 2025

Язык: Английский

Процитировано

0
Unveiling New Binding Sites and Allosteric Regulation Mechanisms of LSD1 for Novel Therapeutics DOI
Kecheng Yang, Jinbo Xiong,

Yuting Shi

и другие.

Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Май 16, 2025

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

Язык: Английский

Процитировано

0