Cooperativity, negative

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. 

The Hill plot is log (B (Bnu>. - B)) vs. log [L], As noted earlier, the slope of the Hill plot (the Hill coefficient, H) is of particular utility. If the equation holds, a straight line of slope = 1 should be obtained. A value greater than 1 may indicate positive cooperativity, and a slope less than 1 either negative cooperativity or commonly the presence of sites with different affinities. The data of Problem 5.1 are also presented as a Hill plot in Figure 5.10. 

In Chapter 1 (Section 1.2.4.3), the Hill equation and the Hill coefficient, nH, are described. Hill coefficients greater than or less than unity are often interpreted as indicating positive or negative cooperativity, respectively, in the relationship between receptor occupancy and response. For example, positive cooperativity could arise due to amplification in a transduction mechanism mediated by G-proteins and changes in cell calcium concentration. 

Both secondary active transport and positive cooperativity effects enhance carrier-mediated solute flux, in contrast to negative cooperativity and inhibition phenomena, which depress this flux. Most secondary active transport in intestinal epithelia is driven by transmembrane ion gradients in which an inorganic cation is cotransported with the solute (usually a nutrient or inorganic anion). Carriers which translocate more than one solute species in the same direction across the membrane are referred to as cotransporters. Carriers which translocate different solutes in opposite directions across the membrane are called countertransporters or exchangers (Figs. 10 and 11). 

Hill Plots Show Evidence of Increasing Negative Cooperativity 153... 

Implications of Increasing Negative Cooperativity and Decreasing Favorable Binding... 

T. K. Dam, R. Roy, D. Page, and C. F. Brewer, Negative cooperativity associated with binding of multivalent carbohydrates to lectins. Thermodynamic analysis of the multivalency effect Biochemistry, 41 (2002) 1351-1358. 

Positive cooperativity means that the reaction of substrate with one active site makes it easier for another substrate to react at another active site. Negative cooperativity means that the reaction of a substrate with one active site makes it harder for substrate to react at the other active site(s). 

COOPERATIVE ENZYMES do not show a hyperbolic dependence of the velocity on substrate concentration. If the binding of one substrate increases the affinity of an oligomeric enzyme for binding of the next substrate, the enzyme shows positive cooperativity. If the first substrate makes it harder to bind the second substrate, the enzyme is negatively cooperative. 

Vmax is S0.5. Enzymes that are positively cooperative are very sensitive to changes of substrate near the S0 5. This makes the enzyme behave more like an on-off switch and is useful metabolically to provide a large change in velocity in response to a small change in substrate concentration. Negative cooperativity causes the velocity to be rather insensitive to changes in substrate concentration near the S0.5-... 

A substrate or effector that binds preferentially to the R state increases the concentration of the R state at equilibrium. This can only happen if, in the absence of substrate or effector, the enzyme is predominantly in the T state. If the enzyme were predominantly in the R state to begin with, it would already have increased affinity for the substrate and there would be no allosteric or cooperative effects. Consequently, the MWC model cannot account for negative cooperativity (but this is rare anyway). 

In the case of polynuclear metal cluster SCO complexes in the solid state, there will be intra-cluster, as well as inter-cluster cooperativity. To eliminate inter-cluster effects totally, studies must be made in dilute solutions. Williams et al. have done just this for a dinuclear [Fe(II)2L3] helicate complex which does not contain a good superexchange pathway between the Fe(II) centre but, rather, three flexible bis-bidentate ligands. A very broad, two step, SCO was observed (LS-LS<->LS-HS<->HS-HS) and fitted to a model for negative cooperativity in which subtle structural changes around each Fe oc-... 

Limbird, L. E., Meyts, P. D., and Lefkowitz, R. J. (1975) Beta-adrenergic receptors evidence for negative cooperativity. Biochem. Biophys. Res. Commun. 64,1160-1168. 

Chazenbalk, G. D Kakinuma, A., Jaume, J. C., McLachlan, S. M., and Rapoport, B. (1996) Evidence for negative cooperativity among human thyrotropin receptors overexpressed in mammalian cells. Endocrinology 137,4586-4591. 

Pizard, A., Marchetti, J., Allegrini, J., Alhenc-Gelas, F., and Rajerison, R. M. (1998) Negative cooperativity in the human bradykinin B2 receptor. J. Biol. Chem. 273, 1309-1315. 

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