Journal
ACS OMEGA
Volume 5, Issue 8, Pages 3979-3995Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsomega.9b03493
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Funding
- Swedish Research Council [2016-05160, D0571301]
- European Molecular Biology Laboratory (EMBL)
- European Community's Seventh Framework Programme (FP7/2007-2013) under BioStruct-X [283570]
- Swedish Research Council [2016-05160] Funding Source: Swedish Research Council
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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 mu M) 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.
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