Structural insight into inhibitors of flavin adenine dinucleotide-dependent lysine demethylases

ABSTRACT

Until 2004, many researchers believed that protein methylation in eukaryotic cells was an irreversible reaction. However, the discovery of lysine-specific demethylase 1 in 2004 drastically changed this view and the concept of chromatin regulation. Since then, the enzymes responsible for lysine demethylation and their cellular substrates, biological significance, and selective regulation have become major research topics in epigenetics and chromatin biology. Many cell-permeable inhibitors for lysine demethylases have been developed, including both target-specific and nonspecific inhibitors. Structural understanding of how these inhibitors bind to lysine demethylases is crucial both for validation of the inhibitors as chemical probes and for the rational design of more potent, target-specific inhibitors. This review focuses on published small-molecule inhibitors targeted at the two flavin adenine dinucleotide-dependent lysine demethylases, lysine-specific demethylases 1 and 2, and how the inhibitors interact with the tertiary structures of the enzymes.

KEYWORDS:

• Chromatin
• crystal structure
• epigenetics
• FAD
• histone
• LSD1
• LSD2
• nucleosome
• transcription

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Acknowledgments

We thank Prof. Naoki Umezawa (Nagoya City University) for critical reading of the manuscript, and Dr. Takehiro Fukami and Ms. Mayuko Yasuda for the investigation of clinical studies. This study was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (no. JP16H05089) and by the Japan Science and Technology Agency PRESTO program.