Structural basis of LSD1-CoREST selectivity in histone H3 recognition

J Biol Chem. 2007 Jul 13;282(28):20070-4. doi: 10.1074/jbc.C700100200. Epub 2007 May 30.

Abstract

Histone demethylase LSD1 regulates transcription by demethylating Lys(4) of histone H3. The crystal structure of the enzyme in complex with CoREST and a substrate-like peptide inhibitor highlights an intricate network of interactions and a folded conformation of the bound peptide. The core of the peptide structure is formed by Arg(2), Gln(5), and Ser(10), which are engaged in specific intramolecular H-bonds. Several charged side chains on the surface of the substrate-binding pocket establish electrostatic interactions with the peptide. The three-dimensional structure predicts that methylated Lys(4) binds in a solvent inaccessible position in front of the flavin cofactor. This geometry is fully consistent with the demethylation reaction being catalyzed through a flavin-mediated oxidation of the substrate amino-methyl group. These features dictate the exquisite substrate specificity of LSD1 and provide a structural framework to explain the fine tuning of its catalytic activity and the active role of CoREST in substrate recognition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Co-Repressor Proteins
  • Crystallography, X-Ray
  • DNA-Binding Proteins / chemistry*
  • DNA-Binding Proteins / metabolism
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Flavins / chemistry
  • Flavins / metabolism
  • Histone Demethylases
  • Histones / chemistry*
  • Histones / metabolism
  • Mice
  • Multienzyme Complexes / chemistry*
  • Multienzyme Complexes / metabolism
  • Nerve Tissue Proteins / chemistry*
  • Nerve Tissue Proteins / metabolism
  • Oxidation-Reduction
  • Oxidoreductases, N-Demethylating / chemistry*
  • Oxidoreductases, N-Demethylating / metabolism
  • Peptides / chemistry*
  • Peptides / metabolism
  • Protein Binding
  • Protein Structure, Quaternary
  • Repressor Proteins / chemistry*
  • Repressor Proteins / metabolism
  • Substrate Specificity

Substances

  • Co-Repressor Proteins
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Flavins
  • Histones
  • Multienzyme Complexes
  • Nerve Tissue Proteins
  • Peptides
  • Rcor2 protein, mouse
  • Repressor Proteins
  • Histone Demethylases
  • KDM1a protein, mouse
  • Oxidoreductases, N-Demethylating

Associated data

  • PDB/2V1D