The combinatorial assembly of protein complexes is at the heart of chromatin biology. Lysine demethylaseLSD1(KDM1A)/CoREST beautifully exemplifies this concept. The active site of the enzyme tightly associates to the N-terminaldomain of transcription factors of the SNAIL1 family, which therefore can competitively inhibit the binding of the N-terminal tailof the histone substrate. Our enzymatic, crystallographic, spectroscopic, and computational studies reveal that LSD1/CoRESTcan bind to a hexapeptide derived from the SNAIL sequence through recognition of a positively chargedα-helical turn that formsupon binding to the enzyme. Variations in sequence and length of this six amino acid ligand modulate affinities enabling the samebinding site to differentially interact with proteins that exert distinct biological functions. The discovered short peptide inhibitorsexhibit antiproliferative activities and lay the foundation for the development of peptidomimetic small molecule inhibitors ofLSD1