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Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Allosteric regulation (or control) means the influence of an effector molecule on an enzyme and plays a role in cell signaling (long-range allosteric effects); it binds at a site other than the enzyme’s active site, the allosteric site. This is often accompanied by conformational changes involving protein dynamics. Effector molecules either cause positive allosteric modulation (allosteric activation) or negative allosteric modulation (allosteric inhibition) and are in a broader sense of importance for conformational perturbations on cellular functions and disease states; in other words the allosteric change in one protein may affect the behavior of other proteins downstream. Non-competitive inhibition always means allosteric inhibition but not all allosteric inhibitors act non-competitive. For models explaining the allosteric effect see Monod et al. (1965; concerted model) and Koshland et al. (1966, sequential model).
Enzyme Catalysis
Published in Harvey W. Blanch, Douglas S. Clark, Biochemical Engineering, 1997
Harvey W. Blanch, Douglas S. Clark
Studies on the cooperativity phenomenon in the binding of ligands to proteins led to the observations of rate cooperativity with enzymes and the concept of allosteric regulation. In 1965, Monod, Changeux, and Wyman proposed a concerted symmetry model to explain these rate cooperativity effects. This model and the related model of Koshland, Némethy and Filmer are based on the concept that each protomer can exist in two conformational forms: a T-form (or tensed form) that can only exist in the absence of bound ligand and an R-form (or relaxed form) that exists when ligand is bound to the protomer but is also present in the absence of ligand. It is assumed that the most stable states are those where all the protomers exist in the same form (either T or R ) and these are consequently the predominant forms of the protein. Thus no hybrid states (i.e proteins containing mixes of T and R forms) will be present. In the absence of the ligand, the two conformational forms of the protein will be in equilibrium, and this equilibrium is disturbed by the binding of the ligand. The MCW model assumes the preexistence of conformational equilibrium and thus differs from others which assume that it is the binding of the ligand which induces the conformational change in the protein.
Ligand Binding to Macromolecules
Published in Jean-Louis Burgot, Thermodynamics in Bioenergetics, 2019
Originally, the term “allosteric” was used for some enzymes, so-called regulatory enzymes, where an effector binds to a site other than the active one and thereby changes the properties of the active site. (Regulatory, see Chapter 30). An (allosteric) effector is generally a small metabolite or cofactor which can modulate the activity of regulatory enzymes.
Subsets of adjacent nodes (SOAN): a fast method for computing suboptimal paths in protein dynamic networks
Published in Molecular Physics, 2021
Thomas Dodd, Xin-Qiu Yao, Donald Hamelberg, Ivaylo Ivanov
Allosteric regulation is a key functional feature of many proteins and protein complexes, involving communication between distal protein regions. The process is initiated by ligand binding or some other structural or dynamic perturbation, which occurs at one site and is subsequently propagated through the protein to influence the activities at a distal site. Knowledge of allosteric communication mechanisms has an impact on the fields of rational drug discovery [1] and protein design [2]. While classical models of allosteric regulation have suggested that a binding event induces substantial conformational changes in the distal site [3,4], other studies have observed allostery in the absence of large-scale conformational change [5,6]. This suggests that subtle differences in dynamics can alter the population distribution of the conformational ensemble without drastically altering the average conformation of the biomolecule.
Exploration of ligand-induced protein conformational alteration, aggregate formation, and its inhibition: A biophysical insight
Published in Preparative Biochemistry and Biotechnology, 2018
Saima Nusrat, Rizwan Hasan Khan
Binding of ligands induces conformational changes in the protein, like loop or domain rearrangements. But, in maximum circumstances, variation in the structure of protein backbone is minor.[50] Some ligands are agonists that stimulate the receptor to initiate ligand binding process,[51] while some ligands are antagonists that block the receptor and act as a competitive inhibitor for such activated ligands, so deactivate the protein. The induction of conformational changes upon ligand binding stimulates the binding affinity of the adjacent molecules interacting with the same receptor and this is called as allosteric regulation.[52,53] In general, the ligand binding is categorized into four groups:
REDAN: relative entropy-based dynamical allosteric network model
Published in Molecular Physics, 2019
As one of its advantages, the GN algorithm is parameter-free, and could be used to determine the optimal number of allosteric communities with maximum modularity of the network [36]. Applying the GN algorithm, it was determined that five communities are the most suitable for PDZ2. Community analysis using GN, KL, and the hybrid GN–KL algorithms are illustrated in Figure 2(c–e), respectively. Usually, the allosteric effects induced by external perturbations alter the protein conformation without changing the secondary structure. Therefore, stable secondary structures including α-helices and β-strands likely belong to same community. Overall, most α-helix and β-strand secondary structures are conserved in the community analyses.