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

Tortorici, Marcello, Borrello, Maria Teresa, Tardugno, Maria, Chiarelli, Laurent R, Pilotto, Simona, Ciossani, Giuseppe, Vellore, Nadeem A, Bailey, Sarah G, Cowan, Jonathan, O'Connell, Maria, Crabb, Simon J, Packham, Graham, Mai, Antonello, Baron, Riccardo, Ganesan, A and Mattevi, Andrea (2013) Protein recognition by short peptide reversible inhibitors of the chromatin-modifying LSD1/CoREST lysine demethylase. ACS Chemical Biology, 8 (8). pp. 1677-1682. ISSN 1554-8937

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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 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.

Item Type: Article
Uncontrolled Keywords: 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
Faculty \ School: Faculty of Science > School of Pharmacy
Faculty of Science
Depositing User: Pure Connector
Date Deposited: 12 May 2014 16:14
Last Modified: 21 Apr 2020 22:57
URI: https://ueaeprints.uea.ac.uk/id/eprint/48268
DOI: 10.1021/cb4001926

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