{"entity": "publication", "iuid": "ccdb900d776c4cbb85ec3f85df42c065", "timestamp": "2026-08-26T22:46:46.530Z", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/ccdb900d776c4cbb85ec3f85df42c065.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/ccdb900d776c4cbb85ec3f85df42c065"}}, "title": "Macrocyclic Peptides Uncover a Novel Binding Mode for Reversible Inhibitors of LSD1.", "authors": [{"family": "Yang", "given": "Jie", "initials": "J"}, {"family": "Talibov", "given": "Vladimir O", "initials": "VO"}, {"family": "Peintner", "given": "Stefan", "initials": "S"}, {"family": "Rhee", "given": "Claire", "initials": "C"}, {"family": "Poongavanam", "given": "Vasanthanathan", "initials": "V"}, {"family": "Geitmann", "given": "Matthis", "initials": "M"}, {"family": "Sebastiano", "given": "Matteo Rossi", "initials": "MR"}, {"family": "Simon", "given": "Bernd", "initials": "B"}, {"family": "Hennig", "given": "Janosch", "initials": "J"}, {"family": "Dobritzsch", "given": "Doreen", "initials": "D"}, {"family": "Danielson", "given": "U Helena", "initials": "UH"}, {"family": "Kihlberg", "given": "Jan", "initials": "J"}], "type": "journal article", "published": "2020-03-03", "journal": {"title": "ACS Omega", "issn": "2470-1343", "volume": "5", "issue": "8", "pages": "3979-3995", "issn-l": "2470-1343"}, "abstract": "Lysine-specific demethylase 1 (LSD1) is an epigenetic enzyme which regulates the methylation of Lys4 of histone 3 (H3) and is overexpressed in certain cancers. We used structures of H3 substrate analogues bound to LSD1 to design macrocyclic peptide inhibitors of LSD1. A linear, Lys4 to Met-substituted, 11-mer (4) was identified as the shortest peptide distinctly interacting with LSD1. It was evolved into macrocycle 31, which was >40 fold more potent (K i = 2.3 \u03bcM) than 4. Linear and macrocyclic peptides exhibited unexpected differences in structure-activity relationships for interactions with LSD1, indicating that they bind LSD1 differently. This was confirmed by the crystal structure of 31 in complex with LSD1-CoREST1, which revealed a novel binding mode at the outer rim of the LSD1 active site and without a direct interaction with FAD. NMR spectroscopy of 31 suggests that macrocyclization restricts its solution ensemble to conformations that include the one in the crystalline complex. Our results provide a solid basis for the design of optimized reversible LSD1 inhibitors.", "doi": "10.1021/acsomega.9b03493", "pmid": "32149225", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC7057333"}], "notes": [], "created": "2026-08-20T08:12:52.376Z", "modified": "2026-08-20T08:13:16.344Z"}