Protein recognition by short peptide reversible inhibitors of the chromatin-modifying LSD1/CoREST lysine demethylase.
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Tortorici M, Borrello MT, Tardugno M, Chiarelli LR, Pilotto S, Ciossani G, Vellore NA, Bailey SG, Cowan J, O'Connell M, Crabb SJ, Packham G, Mai A, Baron R, Ganesan A, Mattevi A
Protein recognition by short peptide reversible inhibitors of the chromatin-modifying LSD1/CoREST lysine demethylase.
ACS Chem Biol. 2013 Aug 16;8(8):1677-82. doi: 10.1021/cb4001926. Epub 2013 Jun 11.
- PubMed ID
- 23721412 [ View in PubMed]
- Abstract
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 alpha-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.