7E0G

Crystal structure of Lysine Specific Demethylase 1 (LSD1) with TAK-418, FAD-adduct

Summary for 7E0G

• Entry DOI: 10.2210/pdb7e0g/pdb
• Descriptor: Lysine-specific histone demethylase 1A, [[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl] [(2R,3S,4S)-5-[5-methanoyl-7,8-dimethyl-2,4-bis(oxidanylidene)-1H-benzo[g]pteridin-10-yl]-2,3,4-tris(oxidanyl)pentyl] hydrogen phosphate, GLYCEROL, ... (6 entities in total)
• Functional Keywords: inhibitor, tak-418, fad-adduct, oxidoreductase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 74947.87

Authors

Oki, H. (deposition date: 2021-01-28, release date: 2021-03-24, Last modification date: 2023-11-29)

Primary citation

Baba, R.,Matsuda, S.,Arakawa, Y.,Yamada, R.,Suzuki, N.,Ando, T.,Oki, H.,Igaki, S.,Daini, M.,Hattori, Y.,Matsumoto, S.,Ito, M.,Nakatani, A.,Kimura, H.
LSD1 enzyme inhibitor TAK-418 unlocks aberrant epigenetic machinery and improves autism symptoms in neurodevelopmental disorder models.
Sci Adv, 7:-, 2021

PubMed Abstract: Persistent epigenetic dysregulation may underlie the pathophysiology of neurodevelopmental disorders, such as autism spectrum disorder (ASD). Here, we show that the inhibition of lysine-specific demethylase 1 (LSD1) enzyme activity normalizes aberrant epigenetic control of gene expression in neurodevelopmental disorders. Maternal exposure to valproate or poly I:C caused sustained dysregulation of gene expression in the brain and ASD-like social and cognitive deficits after birth in rodents. Unexpectedly, a specific inhibitor of LSD1 enzyme activity, 5-((1,2)-2-((cyclopropylmethyl)amino)cyclopropyl)--(tetrahydro-2-pyran-4-yl)thiophene-3-carboxamide hydrochloride (TAK-418), almost completely normalized the dysregulated gene expression in the brain and ameliorated some ASD-like behaviors in these models. The genes modulated by TAK-418 were almost completely different across the models and their ages. These results suggest that LSD1 enzyme activity may stabilize the aberrant epigenetic machinery in neurodevelopmental disorders, and the inhibition of LSD1 enzyme activity may be the master key to recover gene expression homeostasis. TAK-418 may benefit patients with neurodevelopmental disorders.

PubMed: 33712455
DOI: 10.1126/sciadv.aba1187

Experimental method

X-RAY DIFFRACTION (2.25 Å)