Structural basis of histone demethylation by LSD1 revealed by suicide inactivation

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Histone methylation regulates diverse chromatin-templated processes, including transcription. The recent discovery of the first histone lysine–specific demethylase (LSD1) has changed the long-held view that histone methylation is a permanent epigenetic mark. LSD1 is a flavin adenine dinucleotide (FAD)-dependent amine oxidase that demethylates histone H3 Lys4 (H3-K4). However, the mechanism by which LSD1 achieves its substrate specificity is unclear. We report the crystal structure of human LSD1 with a propargylamine-derivatized H3 peptide covalently tethered to FAD. H3 adopts three consecutive γ-turns, enabling an ideal side chain spacing that places its N terminus into an anionic pocket and positions methyl-Lys4 near FAD for catalysis. The LSD1 active site cannot productively accommodate more than three residues on the N-terminal side of the methyllysine, explaining its H3-K4 specificity. The unusual backbone conformation of LSD1-bound H3 suggests a strategy for designing potent LSD1 inhibitors with therapeutic potential.

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Figure 1: Structure of LSD1–CoREST bound to a derivatized histone H3 tail.
Figure 2: LSD1-bound H3 adopts an unusual backbone conformation.
Figure 3: Interactions between LSD1 and H3.

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Results shown in this report are derived from work performed at Argonne National Laboratory, Structural Biology Center, at the Advanced Photon Source. Argonne is operated by UChicago Argonne, LLC, for the US Department of Energy, Office of Biological and Environmental Research. This work was supported in part by grants from the US National Institutes of Health (to P.A.C.), the W.M. Keck Foundation (to H.Y.), the Welch Foundation (to H.Y.) and the Leukemia and Lymphoma Society (to H.Y.)

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Correspondence to Philip A Cole or Hongtao Yu.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Proposed mechanism of LSD1 inactivation by H3 followed by borohydride reduction. (PDF 474 kb)

Supplementary Fig. 2

Spectral analysis of H3-treated GST-LSD1. (PDF 647 kb)

Supplementary Fig. 3

MALDI-TOF spectrum of H3-FAD conjugate. (PDF 682 kb)

Supplementary Fig. 4

Inhibition of GST-LSD1 by H3. (PDF 1112 kb)

Supplementary Table 1

Kinetic analysis of LSD1 mutant enzymes and dimethyl–H3-K4 peptides. (PDF 41 kb)

Supplementary Methods (PDF 104 kb)

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Yang, M., Culhane, J., Szewczuk, L. et al. Structural basis of histone demethylation by LSD1 revealed by suicide inactivation. Nat Struct Mol Biol 14, 535–539 (2007) doi:10.1038/nsmb1255

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