7LKY
Crystal Structure of PHF1 Tudor domain in complex with a peptidomimetic ligand UNC6641
Summary for 7LKY
| Entry DOI | 10.2210/pdb7lky/pdb |
| Descriptor | Isoform 1 of PHD finger protein 1, Peptidomimetic inhibitor UNC6641, ZINC ION, ... (5 entities in total) |
| Functional Keywords | epigenetic reader, peptidomimetic inhibitor, transcription-transcription inhibitor complex, transcription/transcription inhibitor |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 16 |
| Total formula weight | 66294.61 |
| Authors | Liu, J.,Kutateladze, T.G. (deposition date: 2021-02-03, release date: 2021-12-15, Last modification date: 2023-10-18) |
| Primary citation | Engelberg, I.A.,Liu, J.,Norris-Drouin, J.L.,Cholensky, S.H.,Ottavi, S.A.,Frye, S.V.,Kutateladze, T.G.,James, L.I. Discovery of an H3K36me3-Derived Peptidomimetic Ligand with Enhanced Affinity for Plant Homeodomain Finger Protein 1 (PHF1). J.Med.Chem., 64:8510-8522, 2021 Cited by PubMed 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 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. PubMed: 33999620DOI: 10.1021/acs.jmedchem.1c00430 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.85 Å) |
Structure validation
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