Protein recognition by short peptide reversible inhibitors of the chromatin-modifying LSD1/CoREST lysine demethylase

Marcello Tortorici, Maria Teresa Borrello, Maria Tardugno, Laurent R Chiarelli, Simona Pilotto, Giuseppe Ciossani, Nadeem A Vellore, Sarah G Bailey, Jonathan Cowan, Maria O'Connell, Simon J Crabb, Graham Packham, Antonello Mai, Riccardo Baron, A Ganesan, Andrea Mattevi

Research output: Contribution to journalArticlepeer-review

58 Citations (Scopus)


The combinatorial assembly of protein complexes is at the heart of chromatin biology. Lysine demethylase LSD1(KDM1A)/CoREST beautifully exemplifies this concept. The active site of the enzyme tightly associates to the N-terminal domain of transcription factors of the SNAIL1 family, which therefore can competitively inhibit the binding of the N-terminal tail of the histone substrate. Our enzymatic, crystallographic, spectroscopic, and computational studies reveal that LSD1/CoREST can bind to a hexapeptide derived from the SNAIL sequence through recognition of a positively charged α-helical turn that forms upon binding to the enzyme. Variations in sequence and length of this six amino acid ligand modulate affinities enabling the same binding site to differentially interact with proteins that exert distinct biological functions. The discovered short peptide inhibitors exhibit antiproliferative activities and lay the foundation for the development of peptidomimetic small molecule inhibitors of LSD1.
Original languageEnglish
Pages (from-to)1677-1682
Number of pages6
JournalACS Chemical Biology
Issue number8
Early online date30 May 2013
Publication statusPublished - 16 Aug 2013


  • Amino Acid Sequence
  • Binding Sites
  • Cell Proliferation
  • Enzyme Inhibitors
  • Histone Demethylases
  • Humans
  • Models, Molecular
  • Nerve Tissue Proteins
  • Peptides
  • Protein Binding
  • Repressor Proteins
  • Structure-Activity Relationship

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