Macrocyclic Peptides Uncover a Novel Binding Mode for Reversible Inhibitors of LSD1.
ACS Omega
; 5(8): 3979-3995, 2020 Mar 03.
Article
em En
| MEDLINE
| ID: mdl-32149225
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 µM) 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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Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
ACS Omega
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Suécia