7lky
Crystal Structure of PHF1 Tudor domain in complex with a peptidomimetic ligand UNC6641
Structural highlights
FunctionPHF1_HUMAN Transcriptional repressor. May promote methylation of histone H3 on 'Lys-27' by the PRC2/EED-EZH2 complex.[1] [2] Publication Abstract from PubMedPlant 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 K(d) value of 0.96 +/- 0.03 muM 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. Discovery of an H3K36me3-Derived Peptidomimetic Ligand with Enhanced Affinity for Plant Homeodomain Finger Protein 1 (PHF1).,Engelberg IA, Liu J, Norris-Drouin JL, Cholensky SH, Ottavi SA, Frye SV, Kutateladze TG, James LI J Med Chem. 2021 Jun 24;64(12):8510-8522. doi: 10.1021/acs.jmedchem.1c00430. Epub , 2021 May 17. PMID:33999620[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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