Allosteric regulation

In the fields of biochemistry and pharmacology an allosteric regulator (or allosteric modulator) is a substance that binds to a site on an enzyme or receptor distinct from the active site, resulting in a conformational change that alters the protein's activity, either enhancing or inhibiting its function. In contrast, substances that bind directly to an enzyme's active site or the binding site of the endogenous ligand of a receptor are called orthosteric regulators or modulators.

The site to which the effector binds is termed the allosteric site or regulatory site. Allosteric sites allow effectors to bind to the protein, often resulting in a conformational change and/or a change in protein dynamics. Effectors that enhance the protein's activity are referred to as allosteric activators, whereas those that decrease the protein's activity are called allosteric inhibitors.

Allosteric regulations are a natural example of control loops, such as feedback from downstream products or feedforward from upstream substrates. Long-range allostery is especially important in cell signaling. Allosteric regulation is also particularly important in the cell's ability to adjust enzyme activity.

The term allostery comes from the Ancient Greek allos (ἄλλος), "other", and stereos (στερεός), "solid (object)". This is in reference to the fact that the regulatory site of an allosteric protein is physically distinct from its active site. Allostery contrasts with substrate presentation which requires no conformational change for an enzyme's activation. The term orthostery comes from the Ancient Greek orthós (ὀρθός) meaning "straight", "upright", "right" or "correct".

Many allosteric effects can be explained by the concerted MWC model put forth by Monod, Wyman, and Changeux, or by the sequential model (also known as the KNF model) described by Koshland, Nemethy, and Filmer. Both postulate that protein subunits exist in one of two conformations, tensed (T) or relaxed (R), and that relaxed subunits bind substrate more readily than those in the tense state. The two models differ most in their assumptions about subunit interaction and the preexistence of both states. For proteins in which subunits exist in more than two conformations, the allostery landscape model described by Cuendet, Weinstein, and LeVine, can be used. Allosteric regulation may be facilitated by the evolution of large-scale, low-energy conformational changes, which enables long-range allosteric interaction between distant binding sites.

The concerted model of allostery, also referred to as the symmetry model or MWC model, postulates that enzyme subunits are connected in such a way that a conformational change in one subunit is necessarily conferred to all other subunits. Thus, all subunits must exist in the same conformation. The model further holds that, in the absence of any ligand (substrate or otherwise), the equilibrium favors one of the conformational states, T or R. The equilibrium can be shifted to the R or T state through the binding of one ligand (the allosteric effector or ligand) to a site that is different from the active site^{[citation needed]}

The sequential model of allosteric regulation holds that subunits are not connected in such a way that a conformational change in one induces a similar change in the others. Thus, all enzyme subunits do not necessitate the same conformation. Moreover, the sequential model dictates that molecules of a substrate bind via an induced fit protocol. While such an induced fit converts a subunit from the tensed state to relaxed state, it does not propagate the conformational change to adjacent subunits. Instead, substrate-binding at one subunit only slightly alters the structure of other subunits so that their binding sites are more receptive to substrate. To summarize:^{[citation needed]}

The morpheein model of allosteric regulation is a dissociative concerted model.