title: Protein recognition by short peptide reversible inhibitors of the chromatin-modifying LSD1/CoREST lysine demethylase.
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.
authors.affiliation: Department of Biology and Biotechnology, University of Pavia, via Ferrata 9, 27100 Pavia, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Tortorici
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Borrello
authors.forename: Maria
authors.initials: M
authors.lastname: Tardugno
authors.forename: Laurent R
authors.initials: LR
authors.lastname: Chiarelli
authors.forename: Simona
authors.initials: S
authors.lastname: Pilotto
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Ciossani
authors.forename: Nadeem A
authors.initials: NA
authors.lastname: Vellore
authors.forename: Sarah G
authors.initials: SG
authors.lastname: Bailey
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cowan
authors.forename: Maria
authors.initials: M
authors.lastname: O'Connell
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Crabb
authors.forename: Graham
authors.initials: G
authors.lastname: Packham
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
authors.forename: Riccardo
authors.initials: R
authors.lastname: Baron
authors.forename: A
authors.initials: A
authors.lastname: Ganesan
authors.forename: Andrea
authors.initials: A
authors.lastname: Mattevi
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects; D056970:Co-Repressor Proteins; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D056466:Histone Demethylases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D056970:Co-Repressor Proteins; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D010455:Peptides; C121019:RCOR1 protein, human; D012097:Repressor Proteins; D056466:Histone Demethylases; C495195:KDM1A protein, human