Transcription preinitiation complex structure and dynamics provide insight into genetic diseases

Transcription pre-initiation complexes (PIC) are vital assemblies whose function underlies protein gene expression. Cryo-EM advances have begun to uncover their structural organization. Yet, functional analyses are hindered by incompletely modeled regions. Here we integrate all available cryo-EM data to build a practically complete human PIC structural model. This enables simulations that reveal the assembly’s global motions, define PIC partitioning into dynamic communities and delineate how structural modules function together to remodel DNA. We identify key TFIIE–p62 interactions linking core-PIC to TFIIH. P62 rigging interlaces p34, p44 and XPD while capping XPD DNA-binding and ATP-binding sites. PIC kinks and locks substrate DNA, creating negative supercoiling within the Pol II cleft to facilitate promoter opening. Mapping Xeroderma Pigmentosum, Trichothiodystrophy, and Cockayne syndrome disease mutations onto defined communities reveals clustering into three mechanistic classes, affecting TFIIH helicase functions, protein interactions and interface dynamics.