Abstract
Intrinsically disordered proteins/regions (IDPs/IDRs) are proteins or 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. In this study, 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.
Highlights
Disordered proteins/regions (IDPs/IDRs) constitute a significant fraction of the metazoan proteome (Liu et al, 2006; Uversky, 2013)
We found that the commercially supplied compound 1 (ChemDiv 7241-4207) inhibited both Drosophila and human TFIID-directed transcription, but not transcription directed by TATA-binding protein (TBP) (Figure 2B and Figure 2—figure supplement 1A,B), suggesting a TBP-associated factors (TAFs)-specific mechanism of inhibition
Our transcription results suggest that the inhibitory activity targets an evolutionarily conserved TAF subunit of TFIID that is required for a basic function of TFIID during polymerase II (Pol II) transcription initiation in vitro
Summary
Disordered proteins/regions (IDPs/IDRs) constitute a significant fraction of the metazoan proteome (Liu et al, 2006; Uversky, 2013) By virtue of their structural malleability and propensity to interact with multiple-binding partners, these peptide stretches of ∼30 or more amino acid residues have become increasingly recognized for their pivotal and prevalent role in cellular functions including many implicated in human disease pathogenesis (Babu et al, 2011). IDRs are typically composed of low-complexity sequences and are often rich in polar amino acid residues, making them challenging targets for intervention by conventional small-molecule inhibitors, which often require stable hydrophobic-binding pockets (Metallo, 2010). Conceptually, this feature of IDRs may be suitable for interactions with the hydrophilic and periodic metal–oxygen
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