Discovery of an H3K36me3-Derived Peptidomimetic Ligand with Enhanced Affinity for Plant Homeodomain Finger Protein 1 (PHF1).
J Med Chem
; 64(12): 8510-8522, 2021 06 24.
Article
em En
| MEDLINE
| ID: mdl-33999620
ABSTRACT
Plant homeodomain finger protein 1 (PHF1) is an accessory component of the gene silencing complex polycomb repressive complex 2 and recognizes the active chromatin mark, trimethylated lysine 36 of histone H3 (H3K36me3). In addition to its role in transcriptional regulation, PHF1 has been implicated as a driver of endometrial stromal sarcoma and fibromyxoid tumors. We report the discovery and characterization of UNC6641, a peptidomimetic antagonist of the PHF1 Tudor domain which was optimized through in silico modeling and incorporation of non-natural amino acids. UNC6641 binds the PHF1 Tudor domain with a Kd value of 0.96 ± 0.03 µM while also binding the related protein PHF19 with similar potency. A crystal structure of PHF1 in complex with UNC6641, along with NMR and site-directed mutagenesis data, provided insight into the binding mechanism and requirements for binding. Additionally, UNC6641 enabled the development of a high-throughput assay to identify small molecule binders of PHF1.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Ligação a DNA
/
Peptidomiméticos
/
Proteínas do Grupo Polycomb
Limite:
Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article