@article {47034, title = {Chemical perturbation of an intrinsically disordered region of TFIID distinguishes two modes of transcription initiation.}, journal = {eLife}, volume = {4}, year = {2015}, month = {2015 Aug 28}, abstract = {

Intrinsically disordered protein regions (IDRs) are peptide segments that fail to form stable 3-dimensional structures in the absence of partner proteins. They are abundant in eukaryotic proteomes and are often associated with human diseases, but their biological functions have been elusive to study. Here we report the identification of a tin(IV) oxochloride-derived cluster that binds an evolutionarily conserved IDR within the metazoan TFIID transcription complex. Binding arrests an isomerization of promoter-bound TFIID that is required for the engagement of Pol II during the first (de novo) round of transcription initiation. However, the specific chemical probe does not affect reinitiation, which requires the re-entry of Pol II, thus, mechanistically distinguishing these two modes of transcription initiation. This work also suggests a new avenue for targeting the elusive IDRs by harnessing certain features of metal-based complexes for mechanistic studies, and for the development of novel pharmaceutical interventions.

}, issn = {2050-084X}, doi = {10.7554/eLife.07777}, author = {Zhang, Zhengjian and Boskovic, Zarko and Hussain, Mahmud M and Hu, Wenxin and Inouye, Carla and Kim, Han-Je and Abole, A Katherine and Doud, Mary K and Lewis, Timothy A and Koehler, Angela N and Schreiber, Stuart L and Tjian, Robert} } @article {2188, title = {Modular synthesis and preliminary biological evaluation of stereochemically diverse 1,3-dioxanes.}, journal = {Chemistry \& Biology}, volume = {11}, year = {2004}, month = {2004 Sep}, pages = {1279-91}, abstract = {

Modular synthesis and substrate stereocontrol were combined to furnish 18,000 diverse 1,3-dioxanes whose distribution in chemical space rivals that of a reference set of over 2,000 bioactive small molecules. Library quality was assessed at key synthetic stages, culminating in a detailed postsynthesis analysis of purity, yield, and structural characterizability, and the resynthesis of library subsets that did not meet quality standards. The importance of this analysis-resynthesis process is highlighted by the discovery of new biological probes through organismal and protein binding assays, and by determination of the building block and stereochemical basis for their bioactivity. This evaluation of a portion of the 1,3-dioxane library suggests that many additional probes for chemical genetics will be identified as the entire library becomes biologically annotated.

}, keywords = {Amines, Animals, Calmodulin, Combinatorial Chemistry Techniques, Dioxanes, Molecular Structure, Stereoisomerism, Surface Plasmon Resonance, Zebrafish}, issn = {1074-5521}, doi = {10.1016/j.chembiol.2004.07.012}, author = {Wong, Jason C and Sternson, Scott M and Louca, Joseph B and Hong, Roger and Schreiber, Stuart L} } @article {2189, title = {Dissecting glucose signalling with diversity-oriented synthesis and small-molecule microarrays.}, journal = {Nature}, volume = {416}, year = {2002}, month = {2002 Apr 11}, pages = {653-7}, abstract = {

Small molecules that alter protein function provide a means to modulate biological networks with temporal resolution. Here we demonstrate a potentially general and scalable method of identifying such molecules by application to a particular protein, Ure2p, which represses the transcription factors Gln3p and Nil1p. By probing a high-density microarray of small molecules generated by diversity-oriented synthesis with fluorescently labelled Ure2p, we performed 3,780 protein-binding assays in parallel and identified several compounds that bind Ure2p. One compound, which we call uretupamine, specifically activates a glucose-sensitive transcriptional pathway downstream of Ure2p. Whole-genome transcription profiling and chemical epistasis demonstrate the remarkable Ure2p specificity of uretupamine and its ability to modulate the glucose-sensitive subset of genes downstream of Ure2p. These results demonstrate that diversity-oriented synthesis and small-molecule microarrays can be used to identify small molecules that bind to a protein of interest, and that these small molecules can regulate specific functions of the protein.

}, keywords = {Biological, Dioxanes, Dose-Response Relationship, Drug, Fungal, Gene Expression Profiling, Gene Expression Regulation, Genetic, Glucose, Glutathione Peroxidase, Ligands, Messenger, Models, Oligonucleotide Array Sequence Analysis, Oxazoles, Prions, Protein Binding, Repressor Proteins, RNA, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Signal Transduction, Structure-Activity Relationship, Substrate Specificity, Transcription}, issn = {0028-0836}, doi = {10.1038/416653a}, author = {Kuruvilla, Finny G and Shamji, Alykhan F and Sternson, Scott M and Hergenrother, Paul J and Schreiber, Stuart L} } @article {2190, title = {An acid- and base-stable o-nitrobenzyl photolabile linker for solid phase organic synthesis.}, journal = {Tetrahedron Letters}, volume = {39}, year = {1998}, month = {1998 Oct 8}, pages = {7451-54}, abstract = {

The synthesis of an o-nitrobenzyl photolabile linker (1) from o-nitrobenzaldehyde is described, and the efficiency of its light-mediated (365 nm) cleavage is found to be comparable to related, previously developed systems. In contrast, 1 is shown to be stable to acid, base, and Lewis acid/amine combinations while the previously developed linker 2 is shown to degrade under the latter two conditions.

}, issn = {0040-4039}, author = {Sternson, Scott M and Schreiber, Stuart L} }