Negative allosterism

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. 

In this particular case the binding of an alkaline or alkaline earth metal ion to the crown ether decreases the stability of the host with u-allose (negative allosterism), since the conformation of the crown-ether changes due to the metal ion complexation [264-268]. 

Figure 11.6 Schematic representation of the GABAa receptor complex. Examples of the many structurally diverse compounds that act at different sites on the receptor (see text for details). Picrotoxinin, the active component of picrotoxin, and TBPS act as non-competitive antagonists. The barbiturates, steroids and anaesthetics are positive allosteric modulators, as are the benzodiazepine site ligands shown, with the exception of DMCM (negative allosteric modulator) and flumazenil (benzodiazepine site antagonist)...

An example of negative allosteric modulation is the case of the antidepressants, which act as neurotransmitter reuptake blockers for the neurotransmitters norepinephrine and serotonin. This has already been discussed in Chapter 2. When the neurotransmitters norepinephrine and serotonin bind to their own selective receptor sites, they are normally transported back into the presynaptic neuron, as shown in Figure 2-23- Thus the empty reuptake carrier (Fig. 2—20) binds to the neurotransmitter (Fig. 2—21) to begin the transport process (Fig. 2—23). However, when certain antidepressants bind to an allosteric site close to the neurotransmitter transporter (represented as an icon in Figs. 2—22 and 2—24), this causes the neurotransmitter to no longer be able to bind there, thereby blocking synaptic re-... 

An antidepressant drug, which blocks norepinephrine and serotonin reuptake, can be said to modulate in a negative allosteric manner the presynaptic neurotransmitter transporter and thereby block neurotransmitter reuptake (Figs. 2—22 and 2—24). As developed in detail in later chapters, this action may have therapeutic implications for a number of disorders, including depression, panic disorder, and obsessive-compulsive disorder. 

To understand both positive allosteric modulation and negative allosteric modulation. 

Ruel J., Guitton M. J., and Puell J. L. (2002). Negative allosteric modulation of AMPA-preferring receptors by the selective isomer GYKI 53784 (LY303070), a specific non-competitive AMPA antagonist. CNS Drug Rev. 8 235-254. 

This reaction scheme does not take into account the negative allosteric effect of sucrose concentrations above 200 mM or the positive allosteric effect of low concentrations of glucan. 

PFK is activated by AMP (the precursor for ADP and ATP) and by F26BP (which also acts as a positive allosteric effector ) but is inhibited by ATP, citrate and lowered pH ( end products of the pathway), ATP and citrate acting as negative allosteric effectors . In contrast FBPase is activated by citrate (a positive allosteric effector ) and inhibited by the plenty signal F26BP (a negative allosteric effector ). 

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