Fig. 10.

Different allosteric drivers within the same partial agonist can lead to ‘mixed’ conformational states. The cyclic nucleotide cGMP, which forms interactions with a CBD mainly through its base moiety (allosteric driver 1) and its ribose-phosphate moiety (allosteric driver 2), is shown as an example. The base is stabilized in the binding pocket through interactions with the base-binding region and capping lid of the CBD, whereas the phosphate binding cassette (PBC) of the CBD interacts with the ribose-phosphate of the cyclic nucleotide. When the ribose-phosphate is modified, for example, by replacing the equatorial oxygen with a bulkier sulfur, steric clashes with the PBC lead to the PBC sampling the “out” orientation, typical of the inactive conformation. On the other hand, when the base is modified, for example, by introducing additional aromatic motifs, engagement of the capping lid interaction, typical of the active conformation, may be perturbed. If two distinct allosteric drivers within the same ligand preferentially bind different conformations (e.g. active vs. inactive), mixed intermediate states are stabilized.