Coupling allosteric

The equilibrium (dissociation) constant (binding affinity) that is measured might depend upon the receptor affinity state, G protein coupling, allosteric influences, or other factors distal to the actual binding site. According to most present models, this is more likely for agonists than antagonists. 

Glycolysis and the citric acid cycle (to be discussed in Chapter 20) are coupled via phosphofructokinase, because citrate, an intermediate in the citric acid cycle, is an allosteric inhibitor of phosphofructokinase. When the citric acid cycle reaches saturation, glycolysis (which feeds the citric acid cycle under aerobic conditions) slows down. The citric acid cycle directs electrons into the electron transport chain (for the purpose of ATP synthesis in oxidative phosphorylation) and also provides precursor molecules for biosynthetic pathways. Inhibition of glycolysis by citrate ensures that glucose will not be committed to these activities if the citric acid cycle is already saturated. 

Christopoulos, A. (2000). Quantification of allosteric interactions at G-protein coupled receptors using radioligand assays. In Current protocol in pharmacology, edited by Enna, S. J., pp. 1.22.21-1.22.40. Wiley and Sons, New York. 

Lazareno, S., and Birdsall, N. J. M. (1995). Detection, quantitation, and verification of allosteric interactions of agents with labeled and unlabeled ligands at G protein-coupled receptors Interactions of strychnine and acetylcholine at muscarinic receptors. Mol. Pharmacol. 48 362-378. 

FIGURE 7.14 Effect of an allosteric modulator that increases the efficacy of the agonist but has no effect on affinity in two different systems, (a) For full agonists, increases in efficacy produce parallel shifts to the left of the concentration-response curves. Responses modeled with Equation 7.3 with a= 1, , = 5, t = 20, and Ka = 3j.lM. Curves shown for [B]/Kb = 0, 0.3, 1, 3, 10, and 30. (b) In systems with lower receptor density and/or poorer receptor coupling where the agonists does not produce the full system maximal response, an allosteric modulator increases the maximal response and shifts the curves to the left. Responses modeled with Equation 7.3 for the same agonist and same allosteric modulator but in a different tissue (parameters as for A except t= 1). 

Rational design, 148-149, 152 Real-time assays, 83, 88 Receptor(s). See also Drug receptors affinity for, 6, 63 allosteric model of, 143 Clark s work, 3 classical model of, 44-45 concept of, 2-4 conformations, 13-14, 13 Of conservation equation for, 76 constitutive activity of, 49-51 coupling of, 27 definition of, 2 desensitization of, 34 efficacy for, 6... 

Die cytosolic loop between TMs 13 and 14 (KCO I) and TMs 16-17 (KCO II) were identified as critical for KatpCO binding to SURs (Fig. 4d). T1286 and Ml 290 appeared to be particularly important. Close local association of sulfonylurea and KCO binding regions might represent the structural basis for negative allosteric coupling of the sites. 

Goudet C, Binet V, Prezeau L et al (2004) Allosteric modulators of class-C G-Protein coupled receptors open new possibilities for therapeutic application. Drug Discov Today Ther Strat 1 125-133... 

Condensation of CO2, ammonia, and ATP to form carbamoyl phosphate is catalyzed by mitochondrial carbamoyl phosphate synthase I (reaction 1, Figure 29-9). A cytosolic form of this enzyme, carbamoyl phosphate synthase II, uses glutamine rather than ammonia as the nitrogen donor and functions in pyrimidine biosynthesis (see Chapter 34). Carbamoyl phosphate synthase I, the rate-hmiting enzyme of the urea cycle, is active only in the presence of its allosteric activator JV-acetylglutamate, which enhances the affinity of the synthase for ATP. Formation of carbamoyl phosphate requires 2 mol of ATP, one of which serves as a phosphate donor. Conversion of the second ATP to AMP and pyrophosphate, coupled to the hydrolysis of pyrophosphate to orthophosphate, provides the driving... 

An interesting development in this area is the possibility that there could be an endogenous ligand, for these receptors 5-HT-moduline. This is a tetrapeptide that is released from neurons and is claimed to be the first allosteric modulator of a G protein-coupled receptor to be identified so far. Functionally, 5-HT-moduline behaves like a 5-HTib antagonist and so increases terminal release of 5-HT (Massot et al. 1998) and it is thought that this could be an important step in maintaining a sustained increase in release of 5-HT during stress. 

Cortisol concentration Plasma r ligands and allosteric coupling to high-affinity glycine sites (frontal cortex of suicides)... 

Allosteric Modulation of G-Protein-Coupled Receptors Implications for Drug Action Angeliki P. Kourounakis, Pieter van der Klein, and Ad P. I. IJzerman... 

Allosteric Modulation of G-Protein-Coupled Receptors Implications for Drug Action... 

Bhattacharya S, Linden J. The allosteric enhancer, PD 81,723, stabilizes human At adenosine receptor coupling to G proteins. Biochim Biophys Acta 1995 1265 15-21. 

FIG. 4. Model of RyR-mediated Ca2+ release in muscle. Evidence indicates allosteric coupling between the L-type Ca2+ channel and RyRl in skeletal muscle, tight coupling between the channels in cardiac (RyR2), and loose coupling to localized RyR (probably RyR2) in smooth muscle. 

Boileau, A. J., Kucken, A. M Evers, A. R and Czajkowski, C. (1998) Molecular dissection of benzodiazepine binding and allosteric coupling using chimeric gamma-aminobutyric acidA receptor subunits. Mol. Pharmacol. 53, 295-303. 

Pin, J. P, Parmentier, M. L and Prezeau, L. (2001) Positive allosteric modulators for gamma-aminobutyric acidB receptors open new routes for the development of drugs targeting family 3 G protein-coupled receptors. Mol. Pharmacol. 60, 881-884. 

Christopoulos, A. and Kenakin, T. (2002) G protein-coupled receptor allosterism and com-plexing. Pharmacol. Rev. 54,323-374. 

Allosteric coupling, 16 788-789 Allosteric effect, 20 829, 830 Allosteric site, 10 255 Allotropes sulfur, 23 564 tin, 24 786 titanium, 24 838 Alloy 20, 23 784 Alloy 42, 27 841 Alloy broadening, 24 836, 837 Alloy C-276, 23 784 Alloying. See also Alloys... 

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