Receptor cooperativity model

Colquhoun, D. (1973). The relationship between classical and cooperative models for drag action. In A symposium on drug receptors, edited by H. P. Rang, pp. 149-182. University Park Press, Baltimore. 

A model used to explain cooperativity on the basis of ligand-induced changes in conformation that may or may not alter the subunit-subunit interfaces of oligomeric enzymes and receptors. This model has also been referred to as the Adair-Koshland-Nemethy-Filmer model (AKNF model), the induced-fit model, and the sequential model. 

The Chelate Cooperative Model, a = y = 1, c> 0). This model applies to cyclic and multicycHc assembhes in which the constituent cyclic units are identical and behave independent of each other. Every cyclic or multicyclic assembly benefits from chelate cooperativity, measuring the stability of the assembly with respect to the corresponding fijUy saturated open receptor. The chelate cooperative model depends on two reference parameters, K and EM, that allow the calculation of the hypothetical self-assembly constant by using Eq. [51] and assuming a = y = 1. The experimental stability constants of a number of assemblies of different topology, that is, helicates, ladders, >3 and D41,... 

The Allosteric—Chelate Cooperative Model, a 1, y = 1, c> 0). In this model, both allosteric and chelate cooperativity are taken into account. The factor a can be evaluated by studying the interaction of the receptor with a monovalent ligand. An example of an assembly conforming to the allosteric-chelate cooperative model is offered by the supramolecular complex 19 in Hg. 21, whose formation is discussed herein. The following stabihty constants at 25°C in MeCN/CH2Cl2 50 50 (v/v) have been reported log FQa(iT) = 4.5, log Qa(i8) = 8.6 and log... 

The Allosteric-Interannular-Chelate Cooperative Model, (a 1, j 1, c> 0). This model, in which aU the possible types of cooperativity are taken into account, is the most general one. To separate the product aj into its components, the factor a must be evaluated separately by studying the interaction of the receptor with a monovalent ligand. For the sake of illustration, the apphcation of Eq. [51] to test the presence of interannular cooperativity in the self-assembly of the Lehn s double-stranded copper(I) trihelicate 20 (Fig. 22) is discussed in the following. 

This model also can accommodate dose-response curve having Hill coefficients different from unity. This can occur if the stimulus-response coupling mechanism has inherent cooperativity. A general procedure can be used to change any receptor model into a variable slope operational function. This is done by passing the receptor stimulus through a forcing function. 

The operational model allows simulation of cellular response from receptor activation. In some cases, there may be cooperative effects in the stimulus-response cascades translating activation of receptor to tissue response. This can cause the resulting concentration-response curve to have a Hill coefficient different from unity. In general, there is a standard method for doing this namely, reexpressing the receptor occupancy and/or activation expression (defined by the particular molecular model of receptor function) in terms of the operational model with Hill coefficient not equal to unity. The operational model utilizes the concentration of response-producing receptor as the substrate for a Michaelis-Menten type of reaction, given as... 

Samanin, R and Grignaschi, G (1996) Role of 5-hydroxytryptamine receptor subtypes in satiety and animal models of eating disorders. In Drug Receptor Subtypes and Ingestive Behaviour (Eds Cooper, SJ and Clifton, PG), Academic Press, London, pp. 39-58. 

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. 

Weigt, H.et al., The toll-loke receptor-2/6 agonist macrophage-activating lipopeptide-2 cooperates with IFN-gamma to reverse the Th2 skew in an in vitro allergy model, J. Immunol., 172, 6080, 2004. 

Figure 11. Allosteric regulation A conformational change of the active site of an enzyme induced by reversible binding of an effector molecule (A). The model of Monod, Wyman, and Changeux (B) Cooperativity in the MWC is induced by a shift of the equilibrium between the T and R state upon binding of the receptor. Note that the sequential dissociation constants Kr and KR do not change. The T and R states of the enzyme differ in their catalytic properties for substrates. Both plots are adapted from Ref. 140. See color insert.

Linked-function mechanisms for cooperative binding interaction of metabolites and/or drugs, based on the presence of two or more different conformational states of the protein or receptor. See Adair Equation Cooperative Ligand Binding Hemoglobin Hill Equation Plot Koshland-Nemethy-Filmer Model Monod-Wyman-Changeux Model Negative Cooperativity Positive Cooperativity... 

Enzyme active sites and receptors rarely interact with hgands without some attendant change in conformation, and the ability to detect and quantify a conformational change hes at the heart of contemporary biochemical kinetics. See Induced Fit Model Fluorescence Spectroscopy Linked Functions Flemoglobin Cooperativity... 

This method for obtaining components for receptor models has several advantages relative to other methods. First, the component will be determined at the receptor sites, after any condensation, coagulation or fallout during transit has occurred. Second, It may include fugitive emissions from the source as well as ducted emissions. Third, the measurements are made at the same time and with the same device as the ambient sampling. Fourth, the measurements are made on emissions from specific sources In the local area, not just on the same class of source somewhere else. Fifth, the measurements do not require cooperation of the source operators or Intrusion upon their property. 

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