Receptor conformation

Thermodynamically it would be expected that a ligand may not have identical affinity for both receptor conformations. This was an assumption in early formulations of conformational selection. For example, differential affinity for protein conformations was proposed for oxygen binding to hemoglobin [17] and for choline derivatives and nicotinic receptors [18]. Furthermore, assume that these conformations exist in an equilibrium defined by an allosteric constant L (defined as [Ra]/[R-i]) and that a ligand [A] has affinity for both conformations defined by equilibrium association constants Ka and aKa, respectively, for the inactive and active states ... 

Consider a system containing two receptor conformations R, and Ra that coexist in the system according to an allosteric constant denoted L ... 

If the ligand aliosterically affects the affinity of the receptor (antagonist binds to a site separate from that for the tracer ligand) to produce a change in receptor conformation to affect the affinity of the tracer (vide infra) for the tracer ligand (see Chapter 6 for more detail), the displacement curve is given by (see Section 4.6.3)... 

In constitutively active receptor systems (where the baseline is elevated due to spontaneous formation of receptor active states, see Chapter 3 for full discussion), unless the antagonist has identical affinities for the inactive receptor state, the spontaneously formed active state, and the spontaneously G-protein coupled state (three different receptor conformations, see discussion in Chapter 1 on receptor conformation) it will alter the relative concentrations of these species—and in so doing alter the baseline response. If the antagonist has higher affinity for the... 

The debut of the selective AChR agonist (+)-anatoxin-a has provided a new tool for AChR physiology and pharmacology. (+)-Anatoxin not only has high affinity for the nicotinic AChR but it also has high selectivity for nicotinic over muscarinic receptors in the mammalian CNS. Recently, the use of (+)-anatoxin-a was essential to the identification of nicotinic receptors on cultured neurons (4), We are studying the features which allow it to bind with high affinity to the peripheral and central nicotinic receptors and the kinetic effects on receptor conformational... 

Dorns RW (2000) Beyond receptor expression the influence of receptor conformation, density, and affinity in HlV-1 infection. Virology 276(2) 229-237 Dorns RW (2004) Unwelcome guests with master keys how HIV enters cells and how it can be stopped. Top HIV Med 12(4) 100-103... 

Doms RW. Beyond receptor expression the influence of receptor conformation, density, and affinity in HIV-1 infection. Virology 2000 276(2) 229-237. 

Kenakin T., Inverse, protean, and ligand-selective agonism matters of receptor conformation, FASEB J., 15(3), 598-611, 2001. 

In principle, RTK autophosphorylation could occur in cis (within a receptor monomer) or in trans (between two receptors in a dimer). In the first case, ligand binding would cause a change in receptor conformation that would facilitate c/ s-autophosphorylation of tyrosine residues located within or outside the PTK domain. In the second case, no conformational change must occur upon dimerization. The simple proximity effect would provide sufficient opportunity for trans-phosphorylation of tyrosines in the cytoplasmic domain by a second RTK. 

Desensitization can be defined as the tendency of a response to wane, despite the presence of a stimulus of constant intensity (e.g., constant agonist concentration). In the case of the nicotinic ACh receptor, good evidence suggests that desensitization results from a change in receptor conformation to an inactive refractory state (Rang and Ritter, 1970). To describe this in terms of the AChR activation mechanism, we could add a desensitized state to the scheme shown in Eq. (6.2) to give ... 

Henis, Y. I. and Sokolovsky, M. (1983) Muscarinic antagonists induce different receptor conformations in rat adenohypophysis. Mol. Pharmacol. 24, 357-365. 

Binding of the signaling substance to a 7-helix receptor alters the receptor conformation in such a way that the corresponding G protein can attach on the inside of the cell. This causes the a-subunit of the G protein to exchange bound GDP for GTP (1). The G protein then separates from the receptor and dissociates into an a-subunit and a Py-unit. Both of these components bind to other membrane proteins and alter their activity ion channels are opened or closed, and enzymes are activated or inactivated. 

Optical isomerism is the result of a dissymmetry in molecular suhstitution. The basic aspects of optical isomerism are discussed in various textbooks of organic chemistry. Optical isomers (enantiomers) may have different physiological activities from each other provided that their interaction with a receptor or some other effector structure involves the asymmetric carbon atom of the enantiomeric molecule and that the three different substituents on this carbon atom interact with the receptor. The Easson-Stedman hypothesis assumes that a three-point interaction ensures stereospecificity, since only one of the enantiomers will fit the other one is capable of a two-point attachment only, as shown in figure 1.13 for the reaction with a hypothetical planar receptor. However, it is reasonable to assume that receptor stereospecificity can also undergo a change when the receptor conformation is altered by a receptor-drug interaction. 

Indeed, the observation that different agonists can affect which G proteins are activated by a given receptor supports a model where specific receptor conformations may be more or less favorable for coupling to specific G proteins (reviewed in Kenakin, 2003 Perez and Karnik, 2005). In one... 

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