Ternary complex model

The 3D structures of dimeric AtCAD4/5 were obtained in the apo form and as a binary complex with cofactor (NADPH, Figure 33) at 2.0 and 2.6 A resolution, respectively, but not as a ternary complex. " A modeled ternary complex was, however, provisionally obtained with substrate/)-coumaryl aldehyde (14) in the putative substrate-binding pocket. ... 

A classic example of where definitive experimental data necessitated refinement and extension of a model of drug-receptor interaction involved the discovery of constitutive receptor activity in GPCR systems. The state of the art model before this finding was the ternary complex model for GPCRs, a model that cannot accommodate ligand-independent (constitutive) receptor activity. 

With the experimental observation of constitutive activity for GPCRs by Costa and Herz [2], a modification was needed. Subsequently, Samama and colleagues [3] presented the extended ternary complex model to fill the void. This chapter discusses relevant mathematical models and generally offers a linkage between empirical measures of activity and molecular mechanisms. 

The resulting modification is called the extended ternary complex model [3], which describes the spontaneous formation of active state receptor ([Ra]) from an inactive state receptor ([RJ) according to an allosteric constant (L = [Ra]/[RJ). The active state receptor can form a complex with G-protein ([G]) spontaneously to form RaG, or agonist activation can induce formation of a ternary complex ARaG ... 

The extended ternary complex model can take into account the phenomenon of constitutive receptor activity. In genetically engineered systems where receptors can be expressed in high density, Costa and Herz [2] noted that high levels of receptor expression uncovered the existence of a population of spontaneously active receptors and that these receptors produce an elevated basal response in the system. The relevant factor is the ratio of receptors and G-proteins (i.e., elevated levels of receptor cannot yield constitutive activity in the absence of adequate amounts of G-protein, and vice versa). Constitutive activity (due to the [RaG] species) in the absence of ligand ([A] = 0) is expressed as... 

While the extended ternary complex model accounts for the presence of constitutive receptor activity in the absence of ligands, it is thermodynamically incomplete from the standpoint of the interaction of receptor and G-protein species. Specifically, it must be possible from a thermodynamic point of view for the inactive state receptor (ligand bound and unbound) to interact with G-proteins. The cubic ternary complex model accommodates this possibility [23-25]. From a practical point of view, it allows for the potential of receptors (whether unbound or bound by inverse agonists) to sequester G-proteins into a nonsignaling state. 

A schematic representation of receptor systems in terms of the cubic ternary complex model is shown in Figure 3.13. The amount of signaling species (as a fraction of total receptor) as defined by the cubic ternary complex model see Section 3.13.8 is expressed as... 

There are some specific differences between the cubic and extended ternary complex models in terms of predictions of system and drug behavior. The first is that the receptor, either ligand bound or not bound, can form a complex with the G-protein and that this complex need not signal (i.e., [ARiG] and [RjG]). Under these circumstances an inverse agonist (one that stabilizes the inactive state of the receptor) theoretically can form inactive ternary complexes and thus sequester G-proteins away from signaling pathways. There is evidence that this can occur with cannabi-noid receptor [26]. The cubic ternary complex model also... 

FIGURE 3.13 Major components of the cubic ternary complex model [25-27]. The major difference between this model and the extended ternary complex model is the potential for formation of the [ARjG] complex and the [RiG] complex, both receptor/ G-protein complexes that do not induce dissociation of G-protein subunits and subsequent response. Efficacy terms in this model are a, y, and 5. 

The ternary complex model followed by the extended ternary complex model were devised to describe the action of drugs on G-protein-coupled receptors. 

The cubic ternary complex model considers receptors and G-proteins as a synoptic system with some interactions that do not lead to visible activation. 

The extended ternary complex model [23] was conceived after it was clear that receptors could spontaneously activate G-proteins in the absence of agonist. It is an amalgam of the ternary complex model [12] and two-state theory that allows proteins to spontaneously exist in two conformations, each having different properties with respect to other proteins and to ligands. Thus, two receptor species are described [Ra] (active state receptor able to activate G-proteins) and [RJ (inactive state receptors). These coexist according to an allosteric constant (L = [Ra]/[Ri]) ... 

Samama, P., Cotecchia, S., Costa, T., and Lefkowitz, R. J. (1993). A mutation-induced activated state of the p2-adrener-gic receptor Extending the ternary complex model. J. Biol. Chem. 268 4625-4636. 

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

Weiss, J. M., Morgan, P. H., Lutz, M. W., and Kenakin, T. P. (1996a). The cubic ternary complex receptor-occupancy model. I. Model description. J. Theroet. Biol. 178 151-167. 

Cubic ternary complex model, a molecular model (J. Their. Biol 178, 151-167, 1996a 178, 169-182, 1996b 181, 381-397, 1996c) describing the coexistence of two receptor states that can interact with both G-proteins and ligands. The receptor/G-protein complexes may or may not produce a physiological response see Chapter 3.11. 

Extended ternary complex model, a modification of the original ternary complex model for GPCRs (J. Biol. Chem. 268, 4625-4636, 1993) in which the receptor is allowed to spontaneously form an active state that can then couple to G-proteins and produce a physiological response due to constitutive activity. 

Ternary complex (model), this model describes the formation of a complex among a ligand (usually an agonist), a receptor, and a G-protein. Originally described by De Lean and colleagues (J. Biol. Chem. 255, 7108-7117, 1980), it has been modified to include other receptor behaviors (see Chapters 3.8 to 3.11), such as constitutive receptor activity. 

Cubic ternary complex model, 50-52, 56-57 Curve fitting... 

Figure 6. Interconverting receptor model. In the presence of L, membrane R and G become associated to form the ternary complex LRG, which is sequentially interconverted into LR and LRX prior to internalization.

One current model of G-protein receptor activation is the allosteric ternary complex model of Lefkowitz and Costa. The agonist, receptor and G-protein must combine to... 

The simplest model that can describe allosteric interactions at GPCRs is the ternary complex allosteric model [9], As shown in Figure 1, according to this model two parameters define the actions of allosteric agent (X) its affinity for the unoccupied receptor (Kx) and its cooperativity (a) with the ligand (A) that interacts at the primary binding site a < 1 represents negative cooperativity a = 1, no cooperativity a > 1, positive cooperativity. 

However, based on the concept that GPCRs are able to adopt a variety of conformations, an extended model can also be described, as shown in Figure 2. In this extended cubic ternary complex model of receptor activation and modulation, the receptor can interconvert between an active (R) and an inactive conformation (R), each with a different... 

Figure 2 Representation of a "cubic ternary complex" model of allosteric interaction R, the inactive state of the receptor R, the active state of the receptor A, ligand X, allosteric agent. (From Ref. 14.)...

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