Zhang Zhengjian, Boskovic Zarko, Hussain Mahmud M, Hu Wenxin, Inouye Carla, Kim Han-Je, Abole A Katherine, Doud Mary K, Lewis Timothy A, Koehler Angela N, Schreiber Stuart L, Tjian Robert
Transcription Imaging Consortium, Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States.
Department of Chemistry and Chemical Biology, Howard Hughes Medical Institute, Harvard University, Cambridge, United States.
Elife. 2015 Aug 28;4:e07777. doi: 10.7554/eLife.07777.
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.
内在无序蛋白质/区域（IDPs/IDRs）是在没有伴侣蛋白的情况下无法形成稳定三维结构的蛋白质或肽段。它们在真核生物蛋白质组中大量存在，并且常常与人类疾病相关，但对其生物学功能的研究一直难以捉摸。在本研究中，我们报告了一种源自氯氧化锡（IV）的簇的鉴定，该簇与后生动物TFIID转录复合物中一个进化保守的IDR结合。结合阻止了启动子结合的TFIID的异构化，而这种异构化是第一轮（从头）转录起始过程中Pol II参与所必需的。然而，这种特定的化学探针并不影响重新起始，重新起始需要Pol II重新进入，因此，从机制上区分了这两种转录起始模式。这项工作还通过利用金属基复合物的某些特性为针对难以捉摸的IDRs进行机制研究以及开发新型药物干预措施开辟了一条新途径。
