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Published July 2006 | Supplemental Material
Journal Article Open

Crystal structure and mechanism of human lysine-specific demethylase-1


The reversible methylation of specific lysine residues in histone tails is crucial in epigenetic gene regulation. LSD1, the first known lysine-specific demethylase, selectively removes monomethyl and dimethyl, but not trimethyl modifications of Lys4 or Lys9 of histone-3. Here, we present the crystal structure of LSD1 at 2.9-Å resolution. LSD1 forms a highly asymmetric, closely packed domain structure from which a long helical 'tower' domain protrudes. The active site cavity is spacious enough to accommodate several residues of the histone tail substrate, but does not appear capable of recognizing the different methylation states of the substrate lysine. This supports the hypothesis that trimethylated lysine is chemically rather than sterically discriminated. We present a biochemical analysis of LSD1 mutants that identifies crucial residues in the active site cavity and shows the importance of the SWIRM and tower domains for catalysis.

Additional Information

© 2006 Nature Publishing Group. Received 14 April 2006; Accepted 22 May 2006; Published 25 June 2006. We thank the Kazusa DNA Research Institute for the complementary DNA clone of human LSD1, C. Ralston for invaluable support during data collection at the Advanced Light Source, K. Heyman for technical support, A. Patke for discussions, S. Lawrie and S. Etherton for help with editing the manuscript and members of the Blobel laboratory for discussions and comments on the manuscript. N-terminal protein sequencing and peptide synthesis were performed by the Protein Center of the Rockefeller University, and multiangle light-scattering analysis was carried out by the Yale Proteomics Facility. A.H. was supported by a grant from the Leukemia and Lymphoma Society. Author Contributions: P.S. and A.H. designed and performed experiments; P.S., G.B. and A.H. analyzed and interpreted data; A.H. prepared the figures and the manuscript. The authors declare no competing financial interests.

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