Allosterism interaction

It is assumed that receptor dimers can form in the cell membrane (two [R] species to form one [R-R] species). Radioligand [A ] can bind to the receptor [R] to form radioactive complexes [A R], [A R — AR], and [A R — A R], It is also assumed that there is an allosteric interaction between... 

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. 

Characterization of the allosteric interactions between antagonists and amiloride at the human ajA-adrenergic receptor. Mol. Pharmacol. 53 916-925. 

Kenakin, T. P., and Boselli, C. (1989). Pharmacologic discrimination between receptor heterogeneity and allosteric interaction Resultant analysis of gallamine and pirenzeipine antagonism of muscarinic responses in rat trachea. J. Pharmacol. Exp. Ther. 250 944—952. 

A basic concept in receptor pharmacology is the idea of orthosteric and allosteric interaction. Orthosteric interaction occurs when two molecules compete for a single binding domain on the receptor. With allosteric interactions two molecules each have their own binding domain on the receptor and the two interact through effects on the protein (conformational change). Tims, with orthosteric interactions only one molecule may occupy the receptor at any one instant whereas with allosteric interactions both molecules can bind to the receptor at the same time. There are implications for... 

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. 

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.)...

Allosteric interactions on GPCRs have been observed for the muscarinic [11-13], adenosine Ai [14], a2A-adrenergic [15-17], and dopamine D2 receptor [18]. This chapter focuses only on two allosteric phenomena, as well as their potential for therapeutic exploitation that on the muscarinic receptor and that on the adenosine receptor. 

Christopoulos A, Lanzafame A, Michelson E. Allosteric interactions at muscarinic cholinoceptors. Clin Exp Pharmacol Physiol 1998 25 185-194. 

Gharagozloo P, Lazareno S, Popham A, Birdsall N. Allosteric interactions of quaternary strychnine and brucine derivatives with muscarinic acetylcholine receptors. J Med Chem 1999 42 438-445. 

Galvez, T Duthey, B., Kniazelf, J., et al. (2001) Allosteric interactions between GB1 and GB2 subunits are required for optimal GABAb receptor function. EMBO J. 20, 2152-2159. 

Brown GB, Gaupp JE, Olsen RW (1988) Pyrethroid insecticides stereospecific allosteric interaction with the batrachotoxinin-a benzoate binding site of mammalian voltage-sensitive sodium channels. Mol Pharmacol 34 54-59... 

In the following, we mainly use variants of the functional form given in Eq. (56) to describe cooperativity and allosteric regulation in metabolic systems. In particular, within Section VII.C, we discuss a general functional form of rate equations, including allosteric interaction... 

This equation is formally analogous to Hill s empirical equation (Hill, 1910) which is employed to rationalize allosteric interactions in multienzyme systems. 

When binding of a substrate molecule at an enzyme active site promotes substrate binding at other sites, this is called positive homotropic behavior (one of the allosteric interactions). When this co-operative phenomenon is caused by a compound other than the substrate, the behavior is designated as a positive heterotropic response. Equation (6) explains some of the profile of rate constant vs. detergent concentration. Thus, Piszkiewicz claims that micelle-catalyzed reactions can be conceived as models of allosteric enzymes. A major factor which causes the different kinetic behavior [i.e. (4) vs. (5)] will be the hydrophobic nature of substrate. If a substrate molecule does not perturb the micellar structure extensively, the classical formulation of (4) is derived. On the other hand, the allosteric kinetics of (5) will be found if a hydrophobic substrate molecule can induce micellization. 

If the method used to initiate the dissociation affects the measured dissociation rate constant, allosteric interactions within the ligand-receptor complex may be implicated. 

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