title: Catalytic mechanism investigation of lysine-specific demethylase 1 (LSD1): a computational study.
abstract: Lysine-specific demethylase 1 (LSD1), the first identified histone demethylase, is a flavin-dependent amine oxidase which specifically demethylates mono- or dimethylated H3K4 and H3K9 via a redox process. It participates in a broad spectrum of biological processes and is of high importance in cell proliferation, adipogenesis, spermatogenesis, chromosome segregation and embryonic development. To date, as a potential drug target for discovering anti-tumor drugs, the medical significance of LSD1 has been greatly appreciated. However, the catalytic mechanism for the rate-limiting reductive half-reaction in demethylation remains controversial. By employing a combined computational approach including molecular modeling, molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculations, the catalytic mechanism of dimethylated H3K4 demethylation by LSD1 was characterized in details. The three-dimensional (3D) model of the complex was composed of LSD1, CoREST, and histone substrate. A 30-ns MD simulation of the model highlights the pivotal role of the conserved Tyr761 and lysine-water-flavin motif in properly orienting flavin adenine dinucleotide (FAD) with respect to substrate. The synergy of the two factors effectively stabilizes the catalytic environment and facilitated the demethylation reaction. On the basis of the reasonable consistence between simulation results and available mutagenesis data, QM/MM strategy was further employed to probe the catalytic mechanism of the reductive half-reaction in demethylation. The characteristics of the demethylation pathway determined by the potential energy surface and charge distribution analysis indicates that this reaction belongs to the direct hydride transfer mechanism. Our study provides insights into the LSD1 mechanism of reductive half-reaction in demethylation and has important implications for the discovery of regulators against LSD1 enzymes.
authors: State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors: Xiangqian
authors: X
authors: Kong
authors: Sisheng
authors: S
authors: Ouyang
authors: Zhongjie
authors: Z
authors: Liang
authors: Junyan
authors: J
authors: Lu
authors: Liang
authors: L
authors: Chen
authors: Bairong
authors: B
authors: Shen
authors: Donghai
authors: D
authors: Li
authors: Mingyue
authors: M
authors: Zheng
authors: Keqin Kathy
authors: KK
authors: Li
authors: Cheng
authors: C
authors: Luo
authors: Hualiang
authors: H
authors: Jiang
mesh_terms: D019295:Computational Biology / Q000379:methods*; D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism; D056466:Histone Demethylases / Q000378:metabolism*; D006801:Humans; D056004:Molecular Dynamics Simulation
chemical_list: D005182:Flavin-Adenine Dinucleotide; D056466:Histone Demethylases; C495195:KDM1A protein, human