Journal
ACS CHEMICAL BIOLOGY
Volume 8, Issue 8, Pages 1677-1682Publisher
AMER CHEMICAL SOC
DOI: 10.1021/cb4001926
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Funding
- Department of Medicinal Chemistry at the University of Utah, Fondazione Cariplo [2010.0778]
- Associazione Italiana Ricerca sul Cancro [IG-11342]
- MIUR (Epigen)
- University of East Anglia
- COST Action TD0905 Epigenetics: Bench to Bedside
- NSF [OCI-1053575]
- Direct For Computer & Info Scie & Enginr
- Office of Advanced Cyberinfrastructure (OAC) [0910735] Funding Source: National Science Foundation
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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.
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