Allosteric mechanism

As noted previously, in all cases these various functions describe an inverse sigmoidal curve between the displacing ligand and the signal. Therefore, the mechanism of interaction cannot be determined from a single displacement curve. However, observation of a pattern of such curves obtained at different tracer ligand concentrations (range of [A ] values) may indicate whether the displacements are due to a competitive, noncompetitive, or allosteric mechanism. 

Figure 6.10c, this indicates a possible allosteric mechanism whereby a saturation of binding to an allosteric site is operative. This is dealt with further on in this chapter. 

Another particularly unique aspect of allosteric mechanisms is that they can be very probe specific (i.e., a conformational change that is catastrophic for one receptor... 

It can be seen from this example that the inhibition curve shifts to the left with increasing concentration of agonist, indicating an allosteric mechanism whereby the modulator blocks receptor signaling but increases the affinity of the receptor for the agonist. 

Substances that do not target the active site but display inhibition by allosteric mechanisms are associated with a lower risk of unwanted interference with related cellular enzymes. Allosteric inhibition of the viral polymerase is employed in the case of HIV-1 nonnucleosidic RT inhibitors (NNRTl, see chapter by Zimmermann et al., this volume) bind outside the RT active site and act by blocking a conformational change of the enzyme essential for catalysis. A potential disadvantage of targeting regions distant from the active site is that these may be subject to a lower selective pressure for sequence conservation than the active site itself, which can lower the threshold for escape of the virus by mutation. 

Bettati S et al Allosteric mechanism of haemoglobin Rupture of salt-bridges raises the oxygen affinity of the T-structure. J Mol Biol 1998 281 581. 

The principal enzymes controlling glycogen metabolism—glycogen phosphorylase and glycogen synthase— are regulated by allosteric mechanisms and covalent modifications due to reversible phosphorylation and... 

Thus, Ca " controls skeletal muscle contraction and relaxation by an allosteric mechanism mediated by TpC, Tpl, TpT, tropomyosin, and F-actin. 

MDA. However, the competitive inhibition observed at higher NMDA concentrations may indicate that NMDA binding can influence the conformation of the PCP/sigma recognition site via an allosteric mechanism. 

Furthermore, these allosteric effects were shown to be truly subtype specific, depending on the nature of the allosteric modulating compound. Thus, alcuronium exerts positive copperativity with [3H]NMS at the M2 and M4 but not at the Mi and M3 receptors [26,27], while other neuromuscular junction blockers such as stercuronium, pancuronium, and d-tubocurarine have been shown to exhibit their effects via an allosteric mechanism specifically on the M2 receptors [28-30]. 

Levitzki, A., 1978, Quantitative Aspects of Allosteric Mechanisms, Springer-Verlag, New York. McCoy, L. L., 1967, J. Am. Chem. Soc. 89 1673. 

Applications in infrared spectroscopy A and B bands, iron-coordinated CO, 232, 186-187 application to allosteric mechanisms, 249, 566 bacteriorhodopsin, 246, 9, 380-381 caged compounds, 246, 6, 520-521 DNA [base pair formation, 246, 506 conformation, 246, 506-507 denaturation thermodynamics, 246, 506 ligand interactions, 246, 6, 507 sample requirements, 246, 506] fatty acyl ester determination in small cell samples, 233,... 

A central event in the allosteric mechanism is the rotation of the dimers relative to each other. The movement is coupled with the conformational change of all four binding sites for fructose-6-P, since this is foimd at the dimer interace. 

Phosphorylation of glycogen phosphorylase is the initiator for the coupled conformational changes, which are coimmmicated over a large distance to the active site. Similar to the allosteric mechanism of phophofructokinase, the inter-subunit contact sinfaces play a decisive role for the communication between the phosphorylation site... 

Several cases are described (Cohen et ah, 1995) in which binding of an SH2-containing enzyme to an activated receptor tyrosine kinase leads to increased catalytic activity of the enzyme. Examples are the PI3-kinase and phospholipase Oy. The mechanism of activation is not clear. It is possible, however, that the basis is an allosteric mechanism, as is assumed for activation of Src tyrosine kinase. The Src kinase can be phosphoryla-... 

Zhang X, Gureasko J, Shen K et al. An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Ce//2006 125 1137-1149. 

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