7k6r
Crystal structure of the bromodomain (BD) of human Bromodomain and PHD finger-containing Transcription Factor (BPTF) bound to GSK4027
Structural highlights
FunctionBPTF_HUMAN Histone-binding component of NURF (nucleosome-remodeling factor), a complex which catalyzes ATP-dependent nucleosome sliding and facilitates transcription of chromatin. Specifically recognizes H3 tails trimethylated on 'Lys-4' (H3K4me3), which mark transcription start sites of virtually all active genes. May also regulate transcription through direct binding to DNA or transcription factors. Publication Abstract from PubMedBromodomain-containing proteins regulate transcription through protein-protein interactions with chromatin and serve as scaffolding proteins for recruiting essential members of the transcriptional machinery. One such protein is the bromodomain and PHD-containing transcription factor (BPTF), the largest member of the nucleosome remodeling complex, NURF. Despite an emerging role for BPTF in regulating a diverse set of cancers, small molecule development for inhibiting the BPTF bromodomain has been lacking. Here we cross-validate three complementary biophysical assays to further the discovery of BPTF bromodomain inhibitors for chemical probe development: two direct binding assays (protein-observed 19F (PrOF) NMR and surface plasmon resonance (SPR)) and a competitive inhibition assay (AlphaScreen). We first compare the assays using three small molecules and acetylated histone peptides with reported affinity for the BPTF bromodomain. Using SPR with both unlabeled and fluorinated BPTF, we further determine that there is a minimal effect of 19F incorporation on ligand binding for future PrOF NMR experiments. To guide medicinal chemistry efforts towards chemical probe development, we subsequently evaluate two new BPTF inhibitor scaffolds with our suite of biophysical assays and rank-order compound affinities which could not otherwise be determined by PrOF NMR. Finally, we cocrystallize a subset of small molecule inhibitors and present the first published small molecule-protein structures with the BPTF bromodomain. We envision the biophysical assays described here and the structural insights from the crystallography will guide researchers towards developing selective and potent BPTF bromodomain inhibitors. New inhibitors for the BPTF bromodomain enabled by structural biology and biophysical assay development.,Ycas PD, Zahid H, Chan A, Olson NM, Johnson JA, Talluri SK, Schonbrunn E, Pomerantz WCK Org Biomol Chem. 2020 Jul 15;18(27):5174-5182. doi: 10.1039/d0ob00506a. PMID:32588860[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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