This site features trending Allosteric Regulation-linked items from the web for 7 of August 2019.
Trending Allosteric Regulation news item:
A new therapeutic avenue for treating insomnia: Insomnia is one of the major sleep problems all over the world. However, the most widely prescribed medicines for the treatment of insomnia are plagued by a wide range of adverse effects. Researchers have succeeded in identifying the first positive allosteric modulator for adenosine A2A receptors and found that it induces sleep without affecting cardiovascular function, unlike classic receptor agonists. Their discovery may unlock the development of the next-generation sleeping pill… read the entire news item (from Science Daily)
Featured recent scientific publication on Allosteric Regulation:
Mechanism of beta-2AR regulation by an intracellular positive allosteric modulator: Drugs targeting the orthosteric, primary binding site of G protein–coupled receptors are the most common therapeutics. Allosteric binding sites, elsewhere on the receptors, are less well-defined, and so less exploited clinically. We report the crystal structure of the prototypic beta2-adrenergic receptor in complex with an orthosteric agonist and compound-6FA, a positive allosteric modulator of this receptor. It binds on the receptor’s inner surface in a pocket created by intracellular loop 2 and transmembrane segments 3 and 4, stabilizing the loop in an alpha-helical conformation required to engage the G protein. Structural comparison explains the selectivity of the compound for beta2- over the beta1-adrenergic receptor. Diversity in location, mechanism, and selectivity of allosteric ligands provides potential to expand the range of receptor drugs… read the entire scientific publication (from Science)
Trending tweet on #allosteric:
Background knowledge on Allosteric Regulation:
Allosteric regulation refers to the process for modulating the activity of a protein by the binding of a ligand, called an effector, to a site topographically distinct from the site of the protein, called the “active site,” in which the activity characterizing the protein is carried out, whether catalytic (in the case of enzymes) or binding (in the case of receptors) in nature. The word allosteric, Greek for “other site,” was coined to emphasize this distinctness. The modulation of protein activity is accomplished by the reversible alteration of the protein conformation that accompanies effector binding. Effectors that increase activity are called activators, while those that decrease activity are called inhibitors. For the purposes of this article we will use the term substrate to indicate a ligand bound to the active site of either an enzyme or a receptor that undergoes the characteristic activity of the protein. Allosterism and Cooperativity: Allosteric regulation has been found to be extensive in proteins, particularly in enzymes at key branch points of metabolism and in receptors that must be sensitive to small variation in signals. Although a monomeric protein having one subunit can display allosteric regulation, the great majority of proteins regulated in this manner have multiple subunits, with changes in activity arising from changes in subunit–subunit contacts. A characteristic feature of these regulatory proteins is the occurrence of cooperative interactions for both the substrate and the regulatory ligand. This property renders their function dependent upon threshold concentrations of ligand. COOPERATIVE BINDING OF O2 TO HEMOGLOBIN: Cooperativity may be defined as any process in which an initial event affects subsequent similar events. It was initially identified with the sigmoid plot for the binding of four molecules of O2 to hemoglobin (Hb) (Figure 1), a pseudotetrameric protein that gives red blood cells their color. A similar cooperativity of substrate binding occurs in many allosteric enzymes, leading to sigmoid plots of enzyme activity versus substrate concentration. Hb has the subunit composition a2b2, in which the a- and b-subunits are nearly identical to one another, with each containing a heme group to which O2 binds. The sigmoid plot was explained by the concept that the first molecule of O2 bound makes it easier for subsequent molecules to bind, and so is an example of positive cooperativity. In fact, if the Hb-binding curve is fitted to four successive binding constants, the affinity for the fourth O2 bound is calculated to be 100–1000 times as high as the first O2 bound. In contrast, O2 binding to myoglobin (Mb), a monomeric protein found in vertebrate muscle with no possibility for site-site interaction, follows a rectangular hyperbola plot. An essential feature of the positive cooperativity, shown in Figure 1 for Hb, is that it sharpens the responsiveness of a system to a change in substrate (or effector) concentration. Thus, to go from 10% to 90%, O2 saturation of Mb requires an 81-fold change in O2 concentration, whereas the corresponding change for O2 saturation of Hb requires only a fourfold change. Such responsiveness is obviously desirable in a protein whose activity must be highly regulated… read more (from Encyclopedia of Biological Chemistry, 1st Edition)
Keywords: Allosteric Regulation, #allosteric, myoglobin, pseudotetrameric proteins, allosterism, cooperativity, allosteric ligands, allosteric modulators for adenosine A2A receptors, insomnia.
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