Structural Basis for CoREST-Dependent Demethylation of Nucleosomes by the Human LSD1 Histone Demethylase

Maojun Yang, Christian B. Gocke, Xuelian Luo, Dominika Borek, Diana R. Tomchick, Mischa Machius, Zbyszek Otwinowski, Hongtao Yu

Research output: Contribution to journalArticlepeer-review

246 Scopus citations


Histone methylation regulates diverse chromatin-templated processes, including transcription. Many transcriptional corepressor complexes contain lysine-specific demethylase 1 (LSD1) and CoREST that collaborate to demethylate mono- and dimethylated H3-K4 of nucleosomes. Here, we report the crystal structure of the LSD1-CoREST complex. LSD1-CoREST forms an elongated structure with a long stalk connecting the catalytic domain of LSD1 and the CoREST SANT2 domain. LSD1 recognizes a large segment of the H3 tail through a deep, negatively charged pocket at the active site and possibly a shallow groove on its surface. CoREST SANT2 interacts with DNA. Disruption of the SANT2-DNA interaction diminishes CoREST-dependent demethylation of nucleosomes by LSD1. The shape and dimension of LSD1-CoREST suggest its bivalent binding to nucleosomes, allowing efficient H3-K4 demethylation. This spatially separated, multivalent nucleosome binding mode may apply to other chromatin-modifying enzymes that generally contain multiple nucleosome binding modules.

Original languageEnglish (US)
Pages (from-to)377-387
Number of pages11
JournalMolecular cell
Issue number3
StatePublished - Aug 4 2006


  • DNA

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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