Protein allosteric interactions

Christopoulos, A. (2000). Quantification of allosteric interactions at G-protein coupled receptors using radioligand assays. In Current protocol in pharmacology, edited by Enna, S. J., pp. 1.22.21-1.22.40. Wiley and Sons, New York. 

Lazareno, S., and Birdsall, N. J. M. (1995). Detection, quantitation, and verification of allosteric interactions of agents with labeled and unlabeled ligands at G protein-coupled receptors Interactions of strychnine and acetylcholine at muscarinic receptors. Mol. Pharmacol. 48 362-378. 

A basic concept in receptor pharmacology is the idea of orthosteric and allosteric interaction. Orthosteric interaction occurs when two molecules compete for a single binding domain on the receptor. With allosteric interactions two molecules each have their own binding domain on the receptor and the two interact through effects on the protein (conformational change). Tims, with orthosteric interactions only one molecule may occupy the receptor at any one instant whereas with allosteric interactions both molecules can bind to the receptor at the same time. There are implications for... 

W02002004444>. Compound 153 (Figure 5) was found to modulate intermolecular interactions due to its action on some proteins allosterically <2000W02000001349>. 

The topologically defined region(s) on an enzyme responsible for the binding of substrate(s), coenzymes, metal ions, and protons that directly participate in the chemical transformation catalyzed by an enzyme, ribo-zyme, or catalytic antibody. Active sites need not be part of the same protein subunit, and covalently bound intermediates may interact with several regions on different subunits of a multisubunit enzyme complex. See Lambda (A) Isomers of Metal Ion-Nucleotide Complexes Lock and Key Model of Enzyme Action Low-Barrier Hydrogen Bonds Role in Catalysis Yaga-Ozav /a Plot Yonetani-Theorell Plot Induced-Fit Model Allosteric Interaction... 

X is known, information about binding location. This can be exploited to direct the screen to a particular site on a protein. This location is typically the active site, but the method can also be used to investigate allosteric sites or protein-protein binding interfaces. In the following, we will describe various practical approaches to covalent capture and provide examples of their application in studying protein-ligand interactions and drug discovery. 

There are essentially two types of control mechanisms for biochemical switching allosteric cooperative transition and reversible chemical modification. Allosteric cooperativity, which was discussed in Chapter 4, was discovered in 1965 by Jacques Monod, Jefferies Wyman, and Jean-Picrrc Changeux [143], and independently by Daniel Koshland, George Nemethy and David Filmer [116]. The molecular basis of this phenomenon, which is well understood in terms of three-dimensional protein crystal structures and protein-ligand interaction, is covered in every biochemistry textbook [147] as well as special treatises [215],... 

Figure 9 Two proposed models for allosteric interaction observed in hemoglobin, (a) A sequential model of allosteric interaction. When one O2 molecule binds to a subunit in the T-state, the subunit shifts to R-state and affects the affinity of neighboring subunits for the ligand binding, (b) An MWC two-state concerted model of allosteric interaction. When one O2 molecule binds to a subunit in all T-states, a concerted conformational change occurs to produce a protein with all R-state subimits. Square and circle represent T- and R-state subunits, respectively. Moreover, opened and closed diagrams represent free and O2 bound subunits, respectively...

The metabolic functions of living organisms are maintained by a complex interplay of regulatory networks. Enzymatic activity and gene expression are permanently adapted for an optimum performance and may be completely switched on and off in a reversible manner. Typical mechanisms involved in biological systems include the stimulation and inhibition by control proteins or metabolite molecules, allosteric interactions, proteolytic activation, redox transformations, and reversible covalent bond modifications such as phosphorylation and dephosphorylation (5). 

Other mobile-phase modifiers. In general, any species that binds to SA can be used to modify retention and stereoselectivity on an SA CSP. The observed effects are due to either direct competition with the solutes for binding sites on the protein, or through a change in the conformation of the protein that alters the affinity of the protein for the solute (an allosteric interaction). These interactions present the chromatographer with a broad array of mobile-phase modifiers that can be used to tailor the analytical methods to the solutes. 

When substances that themselves bind to specific sites on SA are added to the mobile phase, competitive displacements, that is, a lowering of k and a, are not the only possibilities. There is also the potential for an allosteric interaction to occur in which the affinity of the protein for the solute is increased by the addition of the modifier. For example, the addition of 10 jiM (S)-WAR to the mobile phase increased the k of the S-enantiomers of lorazepam and lorazepam hemisuccinate by 4 and 72%, respectively (113). The k s of the R-enantiomers were not affected and, therefore, the observed a s increased by 5 and 76%, respectively. These results not only increased the chromatographic separation of the respective enantiomers, but also indicated that there was an allosteric interaction between WAR and S)-Iorazepam and (S)-lorazepam hemisuccinate. 

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