Fig. 2

Anatomy of gene-specific transcription factors and potential ways in which small-molecule drugs could inhibit their function

Minimally, an idealized gene-specific transcription factor contains two distinct domains, a DNA-binding domain and a transactivation (transrepression) domain. Transcription factors that have to dimerize in order to bind to their target DNA sequence additionally contain a dimerization domain. Some transcription factors bear additional domains or regions employed for specific protein/ligand (e.g., hormone) binding. After their biosynthesis in the cytoplasm, such transcription factors have to migrate to the nucleus, dimerize, bind to their target gene promoter, and interact with the basal transcriptional apparatus, consisting of basal transcription factors and Pol II (see also Fig. 1). This sequence of events ultimately causes the enhanced (or suppressed) transcription of the target gene. The process can in principle be regulated at any level, e.g., nuclear transport (A), dimerization (B), DNA binding (C), and transactivation (D), but transcription factor degradation (E) can also be subject to control mechanisms that affect the expression level of the target gene (see text for details). A small-molecule drug (indicated by the red-filled rhomboid, red-filled sphere, red-filled hemisphere, red-filled asterisk, and red asterisk) could interfere with any of the above steps by interacting with the appropriate domain or region, thus inhibiting transcription factor function. Interaction with either the DNA-binding or dimerization domain would inhibit DNA binding, whereas interaction with the transcriptional activation domain could inhibit transactivation, leaving the DNA-binding function unperturbed. Red-filled hemisphere, drug targeted to the DNA-binding domain; red-filled sphere, drug targeted to the dimerization domain; red-filled rhomboid, drug targeted to the transactivation (transrepression) domain; red-filled asterisk, drug designed to bind to the region responsible for nuclear localization; red asterisk, drug designed to bind to the region regulating transcription factor degradation (the latter two sites have been arbitrarily chosen on the surface of the transcription factor molecule). Small red arrows point to the transcription factor domain or region interacting with the corresponding drug (i.e., designed on the basis of its 3-D structure).