9zuk

Crystal structure of BPTF bromodomain bound to BZ1

spinqualitylabelsall models 9zuk, resolution 1.35Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9zuk is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.35Å Ligands: A1C4C Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function BPTF_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 PubMed Bromodomain PHD finger Transcription Factor (BPTF) is an epigenetic regulator implicated in cancer progression. However, despite its oncogenic significance, highly selective and potent inhibitors of the BPTF bromodomain (BRD) with suitable physicochemical properties are lacking. Previously, we reported BZ1, a submicromolar BPTF inhibitor that has off-target activities. Here, we applied comparative structural biology and molecular modeling to design BZ2, a regioisomer of BZ1 with enhanced selectivity for BPTF over other class I BRDs and class-IV BRDs such as BRD7 and BRD9. Crystal structures and computational analyses reveal that differential engagement of water networks and polar interactions drives this selectivity. Functional studies demonstrate that genetic disruption of the BPTF BRD or treatment with BZ2 suppresses neuroblastoma (NB) cell growth. With high potency and improved physicochemical properties, BZ2 provides a valuable tool for probing the biology of BPTF and represents a promising starting point for advancing BPTF-targeted drug development. Differential Water Networks Guide Selectivity Optimization of a Cell Active BPTF Inhibitor in Neuroblastoma.,Babu K, Tsou CJ, Das S, Fan L, Pal A, Sneddon M, Stachowski TR, Samanta P, Nithianantham S, Buchholz C, Zhang S, Fu X, Kathayat RS, Lin W, Li Y, Yang L, Chen T, Fischer M, Shelat AA, Pomerantz WCK Angew Chem Int Ed Engl. 2026 Sep 8:e4580510. doi: 10.1002/anie.4580510. PMID:42711825 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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