A model for a TFIID-containing and Mediator-containing pre-initiation complex (PIC) adapted from ref. 43. Note the additional stabilizing interactions relative to a TATA binding protein (TBP)-nucleated minimal PIC that does not contain Mediator (Fig. 1). Highlighted here is the stabilization of the RPB1 carboxy-terminal domain (CTD), but numerous other subtle, and perhaps dynamic, interactions between the coactivators, RNA polymerase II (Pol II) and general transcription factors (GTFs) also take place, as discussed and referenced in the main text. Additional stabilizing interactions of the PIC might come from promoter proximally bound activators and the downstream +1 nucleosome via TFIID (Fig. 5) and Mediator (not shown; see text). Other general cofactors that may be fulfilling architectural and other roles may also contribute but are not shown (Box 2). CAK, CDK-activating kinase.