Fig. 1

Schematic representation showing how selective nuclear receptor modulation underpins the SPPARM concept. The binding of different ligands to nuclear receptors induces different conformational changes which influence cofactor affinity. Different ligands may share cofactors, resulting in shared biological responses (a) but may also have distinct differences in the cofactor-receptor binding profile (b). Thus, the unique receptor-cofactor binding profile of the ligand is the key determinant of the specificity and potency of receptor binding and in turn modulates gene- and tissue selective effects