**2. Molecular basis for partial agonism**

The shared domain structure of steroid receptors includes a variable N-terminal domain, a highly conserved DNA-binding domain and a moderately conserved ligand-binding domain (LBD). The LBD domain tends to be the primary target for drug-design. The LBD combines a number of functions, including hormone binding, receptor dimerization and binding to other co-modulating proteins that play a role in the control of transcription. These functions have the ability to influence each other, with ligand-binding, as an example; influencing the pattern of co-modulator recruitment. Specifically, gene activation requires the recruitment of co-modulating proteins to a region of the surface of the LBD formed by helices 3/4, 5 and 12. The position of helix-12, as we will discuss, can be influenced by the nature of the ligand bound to the receptor allowing drugs to influence the binding of comodulators and consequently gene activation and the resulting biological effects (Bourguet, Germain, and Gronemeyer, 2000;Egea, Klaholz, and Moras, 2000;Kumar and Thompson, 1999;Weatherman, Fletterick, and Scanlan, 1999).

Understanding the molecular basis for partial agonism is hampered by the difficulty in solving the X-ray structures of steroid-receptors in general and specifically complexes including partial active ligands (Nettles et al, 2008). Full agonists stabilize the receptor, and specifically helix-12, in a conformation suited to binding co-activating proteins and full antagonists stabilize the receptor in a conformation suited to binding co-repressing proteins. The apparent reason for the difficulty in co-crystallizing partial agonists is that they do not fully stabilize the receptor in either conformation, adopting some degree of equilibrium between the two (Nettles et al, 2008;Raaijmakers, Versteegh, and Uitdehaag, 2009). This equilibrium allows partially active compounds to bind unique patterns of co-modulators compared to full agonists and antagonists, resulting in their potentially interesting biological effects. Unfortunately as a result it also renders them poorly suited to cocrystallization studies.

The degree of partial activity (how far from either a full agonist or antagonist response) will go some way to determining the profile of co-modulators which will bind. Additionally, the ratio of co-activators compared to co-repressors in each cell type will influence the biological effect of a partial compound. In cells with a high co-activator concentration we would expect partial compounds to show a greater degree of agonistic activity compared to the same ligand in a cell with a high co-repressor concentration. The limitless combination of ligand partiality and co-modulator distribution appears to be a major contributor to the tissue selective responses of partial compounds.
