Agonist ternary complex binding

DeLean, A., Stadel, J. M. Lefkowitz, R. J. (1980). A ternary complex model explains the agonist-specific binding properties... 

Agonists can produce complex binding profiles due to the formation of different protein species (i.e., ternary complexes with G-proteins). The extent of this phenomenon is related to the magnitude of agonist efficacy and can be used to quantify efficacy. 

Receptor [R] binds to agonist [A] and goes on to form a ternary complex with G-protein [G] ... 

The binding of an agonist to a receptor promotes the formation of a ternary LRG complex and an exchange of guanosine-5 -triphosphate (GTP) for guanosine-5 -diphosphate (GDP) on the G protein. The ternary complex is thus activated, promoting dissociation of LR from G and G into its subunits G and... 

Analysis of the soluble G-bead assembly provides a complementary classification of full and partial agonists, based on their distinct abilities to assemble ternary complexes (LRG). It appears that the behavior of receptors and entire ligand families can be described by the simple ternary complex model alone (Fig. 2A). The analysis provides estimates for the ligand-dependent equilibrium constants that govern the simple ternary complex model. Unique, potentially intermediate, conformational states of the receptor defined by interactions with a particular ligand are characterized by individual binding constants. While these data do not directly show these different conformational states, the bead system appears to act as a... 

Fig. 5. Conceptual schematic of the receptor conformational states elicited by binding to partial (L, ) or full (Ly) agonists, and a depiction of the correlation between the various conformational states and their ability to bind with G proteins. Solid lines show the conformational distributions hypothesized from soluble ternary complex data analyzed by the simple ternary complex model. When a partial agonist binds with a receptor (L R) in this model, the receptor forms a conformational state which has an intermediate affinity for G protein, consequendy leading to formation of intermediate amounts of L RG. On the other hand, the dotted line represents the potential receptor conformations induced by a partial agonist consistent with the extended ternary complex model, which includes the isomerization of receptor between R and R, the only receptor conformation allowed to bind with G protein. For this model, the interactions of a partial agonist with a receptor would result in two populations of ligand-bound receptors with only one (LR ) able to bind with G protein. The x-axis is analogous to the cooperativity factor a.

Agonists bind with higher affinity to the ternary complex than to the binary complex and in addition, stabilize and promote the formation of the ternary complex. The coexistence of these binary and ternary complexes in the membrane provide a molecular basis for the characteristic biphasic, shallow curve of agonist... 

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