5mg2
Crystal structure of the second bromodomain of human TAF1 in complex with BAY-299 chemical probe
Structural highlights
DiseaseTAF1_HUMAN Defects in TAF1 are the cause of dystonia type 3 (DYT3) [MIM:314250; also called X-linked dystonia-parkinsonism (XDP). DYT3 is a X-linked dystonia-parkinsonism disorder. Dystonia is defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures. DYT3 is characterized by severe progressive torsion dystonia followed by parkinsonism. Its prevalence is high in the Philippines. DYT3 has a well-defined pathology of extensive neuronal loss and mosaic gliosis in the striatum (caudate nucleus and putamen) which appears to resemble that in Huntington disease.[1] [2] FunctionTAF1_HUMAN Largest component and core scaffold of the TFIID basal transcription factor complex. Contains novel N- and C-terminal Ser/Thr kinase domains which can autophosphorylate or transphosphorylate other transcription factors. Phosphorylates TP53 on 'Thr-55' which leads to MDM2-mediated degradation of TP53. Phosphorylates GTF2A1 and GTF2F1 on Ser residues. Possesses DNA-binding activity. Essential for progression of the G1 phase of the cell cycle.[3] [4] [5] [6] [7] [8] [9] Publication Abstract from PubMedBromodomains (BD) are readers of lysine acetylation marks present in numerous proteins associated with chromatin. Here we describe a dual inhibitor of the bromodomain and PHD finger (BRPF) family member BRPF2 and the TATA box binding protein-associated factors TAF1 and TAF1L. These proteins are found in large chromatin complexes and play important roles in transcription regulation. The substituted benzoisoquinolinedione series was identified by high-throughput screening, and subsequent structure-activity relationship optimization allowed generation of low nanomolar BRPF2 BD inhibitors with strong selectivity against BRPF1 and BRPF3 BDs. In addition, a strong inhibition of TAF1/TAF1L BD2 was measured for most derivatives. The best compound of the series was BAY-299, which is a very potent, dual inhibitor with an IC50 of 67 nM for BRPF2 BD, 8 nM for TAF1 BD2, and 106 nM for TAF1L BD2. Importantly, no activity was measured for BRD4 BDs. Furthermore, cellular activity was evidenced using a BRPF2- or TAF1-histone H3.3 or H4 interaction assay. Benzoisoquinolinediones as Potent and Selective Inhibitors of BRPF2 and TAF1/TAF1L Bromodomains.,Bouche L, Christ CD, Siegel S, Fernandez-Montalvan AE, Holton SJ, Fedorov O, Ter Laak A, Sugawara T, Stockigt D, Tallant C, Bennett J, Monteiro O, Diaz-Saez L, Siejka P, Meier J, Putter V, Weiske J, Muller S, Huber KVM, Hartung IV, Haendler B J Med Chem. 2017 May 1. doi: 10.1021/acs.jmedchem.7b00306. PMID:28402630[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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