The methylation states of Lys-residues in histones tails affect the functions of chromatin with consequences for expression in healthy and diseased tissues. PHF8 (KDM7B) is a 2-oxoglutarate (2OG) and Fe-dependent human Jumonji C (JmjC) family Nε-methyl lysine demethylases. Activity of KDM7 enzymes is linked to various cancers, including prostate, breast, laryngeal and hypopharyngeal, non-small cell lung, and oesophageal cancer. PHF8 specifically demethylates Nε-dimethylated lysine9 residue of the histone-3 N-terminal tail. The PHF8 enzyme has an unusually simple two domain architecture for JmjC KDMs, indicating they are good models for understanding molecular details of KDM function. Using Quantum Mechanical /Molecular Mechanical (QM/MM) and Molecular Dynamics (MD) methods, the detailed reaction mechanism of demethylation by PHF8 enzyme will be explained. Role of linker region, protein environment, second-sphere residues, inter-domain interactions in catalysis will be revealed.

Computational insights into catalytic mechanism of Nε-methyl lysine demethylation by PHF8

2019 Fall National Meeting

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