title: Chemical perturbation of an intrinsically disordered region of TFIID distinguishes two modes of transcription initiation.
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.
authors: Transcription Imaging Consortium, Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States.
authors: Zhengjian
authors: http://orcid.org/0000-0002-2840-0837
authors: Z
authors: Zhang
authors: Department of Chemistry and Chemical Biology, Howard Hughes Medical Institute, Harvard University, Cambridge, United States.
authors: Zarko
authors: Z
authors: Boskovic
authors: Department of Chemistry and Chemical Biology, Howard Hughes Medical Institute, Harvard University, Cambridge, United States.
authors: Mahmud M
authors: MM
authors: Hussain
authors: Transcription Imaging Consortium, Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States.
authors: Wenxin
authors: W
authors: Hu
authors: Li Ka Shing Center for Biomedical and Health Sciences, Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States.
authors: Carla
authors: C
authors: Inouye
authors: Center for the Science of Therapeutics, Broad Institute, Cambridge, United States.
authors: Han-Je
authors: http://orcid.org/0000-0002-0305-259X
authors: HJ
authors: Kim
authors: Department of Chemistry, University of California, Berkeley, Berkeley, United States.
authors: A Katherine
authors: AK
authors: Abole
authors: Center for the Science of Therapeutics, Broad Institute, Cambridge, United States.
authors: Mary K
authors: MK
authors: Doud
authors: Center for the Science of Therapeutics, Broad Institute, Cambridge, United States.
authors: Timothy A
authors: TA
authors: Lewis
authors: Center for the Science of Therapeutics, Broad Institute, Cambridge, United States.
authors: Angela N
authors: AN
authors: Koehler
authors: Department of Chemistry and Chemical Biology, Howard Hughes Medical Institute, Harvard University, Cambridge, United States.
authors: Stuart L
authors: http://orcid.org/0000-0003-1922-7558
authors: SL
authors: Schreiber
authors: Transcription Imaging Consortium, Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States.
authors: Robert
authors: R
authors: Tjian
mesh_terms: D000818:Animals; D004331:Drosophila melanogaster; D007536:Isomerism; D011487:Protein Conformation / Q000187:drug effects; D012319:RNA Polymerase II / Q000378:metabolism; D017971:Tin Compounds / Q000378:metabolism*; D035362:Transcription Factor TFIID / Q000737:chemistry* / Q000378:metabolism*; D061785:Transcription Initiation, Genetic
chemical_list: D017971:Tin Compounds; D035362:Transcription Factor TFIID; D012319:RNA Polymerase II
keywords: D. melanogaster; biochemistry; chromosomes; conformational isomerization; genes; human; intrinsically disordered proteins/regions; metal oxo complexes; preinitiation complex; transcription factors; transcription reinitiation