Concerted allosteric model

Selected entries from Methods in Enzymology [vol, page(s)] Activation, 64, 177 concerted allosteric model, 64, 173 isotope exchange properties, 64, 10 negative cooperativity, 64, 189 rapid relaxation measurement, 64, 188, 189 sequential model, 64,... 

Concerted opening. Suppose that a channel obeys the concerted allosteric model (MWC model. Section 10,1.5). The binding of ligand to the R state (the open form) is 20 times as tight as to the T state (the closed form). In the absence of ligand, the ratio of closed to open channels is lO. If the channel is a tetramer, what is the fraction of open channels when 1, 2, 3, and 4 ligands are bound ... 

Each of the two enzymes thus behaves as phosphofructokinase in the model considered for glycolytic oscillations (chapter 2). To limit the study to temporal organization phenomena, the system is considered here as spatially homogeneous, as in the case of experiments on glycolytic oscillations (Hess et ai, 1969). In the case where the kinetics of the two enzymes obeys the concerted allosteric model (Monod et al, 1965), the time evolution of the model is governed by the kinetic equations (4.1), which take the form of three nonlinear, ordinary differential equations ... 

In the context of the Monod-Wyman-Changeux concerted-transition model for allosteric effects, one usually considers the effects of specific site occupancy on the behavior of other binding sites. Thus, a more correct... 

Allosteric switching. A substrate binds 100 times as tightly to the R state of an allosteric enzyme as to its T state. Assume that the concerted (MWC) model applies to this enzyme. 

Fipire 4- 4 According to the concerted-symmetry model, an allosteric inhibitor binds preferendaliy to the T form. This causes the velocity curve to become more sigmoidal tvith a higher [S]gj. An allosteric activator mimics the substrate by binding preferentially to the R form. As a result, the velocity curve becomes less sigmoidal (hyperbolic at saturating activator) and fS]oi decreases. These observations can also be explained in terms of the sequential interaction model. 

Figure 4-55 The concerted-symmetry model for an allosteric dimer where S binds exclusively to the R form (c= 0).

Fig. 2. Simple two state allosteric model for qE in which the switch between quenched and unquenched conformation is driven by the effect of protonation and de-epoxidation. In this model LHCll can exist in two states, an unquenched conformation and a quenched conformation. Because the affinity of proton and zeaxanthin binding is greater in the quenched state, the ApH and de-epoxidation state will determine the equilibrium between these states. The existence of co-operativity indicates that these two states consist of a group of LHCll subunits which interact and change conformation in concert. The changed conformation, and intersubunit interaction, may give rise to quenching process itself In this model one or moreofthe different LHCll components may be involved.

For the allosteric model based on a concerted transition between the two conformational states, as considered here in the model for glycolytic oscillations, application of definition (2.27) in the case where the two states of the enzyme differ only by the affinity toward the substrate (0 = 1) leads to expression (2.28) for the Hill coefficient related to saturation of the enzyme by the substrate (Goldbeter, 1976,1977) ... 

The three variables in that model are intracellular ATP (a), intracellular cAMP (j8), and extracellular cAMP (y). We assume that the complex obeys the allosteric model of Monod et al. (1965), i.e. each regulatory or catalytic subunit can exist in two states, one of which has a larger affinity towards its ligand or, in the case of the catalytic subunit, is more active than the other the transition between these two states is concerted. When we etssume, moreover, that the system remains spatially homogeneous (which corresponds to the conditions in continuously stirred cell suspensions), the time evolution of the system is governed by the three ordinary differential equations ... 

The concerted symmetry model is much more versatile than simple sequential models described by Adair or Hill. This model is endowed by the variable values of Kr, L, and c, and therefore may provide explanations for many properties of allosteric enzymes and proteins, including... 

The MWC concerted-symmetry and KNF sequential interaction models may be considered as extreme cases of the more general model shown in Fig. 19. A general model for a four-site allosteric enzyme involves the hybrid oligomers. The first and the fourth column in Fig. 19 represent the concerted-symmetry model. The diagonal represents the sequential interaction model. As shown, there are 25 different types of enzyme forms. If the potential nonequivalent complexes are included (such as, e.g., two different T3RS2), the number raises to 44 possible enzyme forms (Hammes Wu, 1971). 

The MWC model says that in the R state, all the active sites are the same and all have higher substrate affinity than in the T state. If one site is in the R state, all are. In any one protein molecule at any one time, all subunits are supposed to have identical affinities for substrate. Because the transition between the R and the T states happens at the same time to all subunits, the MWC model has been called file concerted model for allosterism and cooperativity. The MWC model invokes this symmetry principle because the modelers saw no compelling reason to think that one of the chemically identical subunits of a protein would have a conformation that was different from the others. Alternative models exist that suggest that each subunit can have a different conformation and different affinities for substrate. Experimentally, examples are known that follow each model. 

FIGURE 16.7 Concerted model for allosteric enzymes. The major steps are (a) and (b). An equilibrium exists between the tight (a) and relaxed (b) forms of the allosteric enzyme. The reactant molecule(s) approaches the reactive site of one of the enzyme sites present in the relaxed form (c). Binding occurs, shifting the equilibrium to the relaxed form(s). The second site is bound (d). 

Monod, J., Wyman, J., Changeux, J.-P. (1965) On the nature of allosteric transitions a plausible model. J. Mol Biol. 12, 88-118. The concerted model was first proposed in this landmark paper. 

Because AMPA receptors function in concert with NMDA receptors, they have been proposed as alternative therapeutic targets in schizophrenia. AMPAkines function as positive allosteric modulators of AMPA receptor-mediated neurotransmission, and facilitate learning and memory in both human (Ingvar et al., 1997) and animal (Hampson et al., 1998) models. Further, these drugs act synergistically with antipsycho-tics to reverse amphetamine-induced hyperactivity (Johnson et al., 1999). 

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