Allosterism, binding

Fig. 21. (a) Diagrammatical representation of an allosteric receptor mechanism (b) allosteric binding of a thymine derivative promoted on uptake (34). 

It is useful to think of the allosteric binding not in terms of deformation of the receptor active site but rather as a lever to lock the receptor into a given conformation. 

However, the testing of a wide range of concentrations of an allosteric antagonist would show the saturation of the allosteric binding site as revealed by an approach to a maximal value for the antagonism. The Schild equation for an allosteric antagonist is given by (see Section 7.8.3)... 

Jakubic, J., Bacakova, L., Lisd, V., El-Fakahany, E. E., and Tucek, S. (1996). Activation of muscarinic acetylcholine receptors via their allosteric binding sites. Proc. Natl. Acad. Sci. USA 93 8705-8709. 

Recently, many NNl of HCV NS5B RNA polymerase have been discovered and these were recently reviewed (Condon et al. 2005). One allosteric binding site has... 

Ellis J. Allosteric binding sites on muscarinic receptors. Drug Dev Res 1997 40 193-204. 

Naerum, L. Norskov-Lauridsen, P. B. Rasmussen, L. Thim, F. C. Wiberg, and K. Lundgren, Characterization of the allosteric binding pocket of human liver fructose 1,6-bisphosphatase by protein crystallography and inhibitor activity studies, Protein Sci. 6 971 (1997). 

Figure 2. Stereoview of the allosteric binding site of fructose 1,6-bisphosphatase and the binding geometry of AMP (yellow).

Malherbe, P. N. K., Knoflach, F Zenner, M. T et al. (2003) Mutational analysis and molecular modeling of the allosteric binding site of a novel, selective, non-competitive antagonist of the metabotropic glutamate 1 receptor. J. Biol. Chem. 278,8340-8347. 

Allosteric binding occurs when two molecules bind to different sites on the target. When the two molecules are identical, it is termed homotropic interaction. If the molecules differ from each other, it is termed heterotropic interaction. Binding is competitive when two different ligand molecules compete for the same site. We discuss ligand binding further in Chapter 3. The specificity of ligand-receptor interaction is illustrated in Exhibit 2.9. 

Hemoglin (Hb) is no doubt the most extensively studied protein, in general, and as an allosteric binding system, in particular. Although the details of its structure... 

Fig. 3.11 Examples of allosteric binding competition. Titration of 5 pM Akt-1 plus 5 pM staurosporine by (A) NGD-28835 and (B) Merck-1 does not yield linear response ratios for the two competing ligands. Asymptotically bound response ratios indicate allosteric binding between these two...

Reviewed in Christopoulos, A. Allosteric binding sites on cell-surface receptors novel targets for drug discovery. Nat. Rev. Drug Discov. 2002, 1, 198-210. 

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