(i) homotropic allosteric interaction when ligand 1 and ligand 2 are the same type of molecule and site 1 and site 2, though topologically distinct, exert the same functional activity;

(ii) heterotropic allosteric interaction when ligand 1 and ligand 2 are different molecules and site 1 and site 2 display a different functional activity. In this case, ligand 2 is called effector and site 2 is called regulatory site.

The most widely known example of an allosteric protein is represented by hemoglobin (Hb), which shows both types of allostery, namely (a) the homotropic interaction among the four molecules of dioxygen binding to the four hemes, giving rise to cooperativity, and (b) the heterotropic interaction between dioxygen binding to the heme and effector molecules, such as 2,3-BPG (which binds at a crevice between the two β-chains) and H⁺ (which protonate several groups functionally relevant). Obviously, homotropic allosteric interactions are only possible for macromolecules displaying multiple active sites, whereas heterotropic allosteric interactions may occur also in macromolecules with only one site 1 and one site 2.

Allosteric interactions may have either activating or inhibitory effects according to whether the presence of ligand 2 on site 2 increases or decreases, respectively, the affinity of ligand 1 for site 1. Energy conservation law demands that the affinity effect is reciprocal for the two interacting sites (that is the effect on the affinity of ligand 2 for site 2 is quantitatively identical when ligand 1 is bound to site 1); the binding free energy difference is called interaction energy.

All dynamic proteins are potentially allosteric and allostery plays crucial roles in all cellular pathways. Furthermore, allosteric interactions may represent a mechanism of the utmost importance for the regulation of drug action and their characterization is a crucial step for determining the selectivity of the drug activity. Therefore, allosteric sites must be considered as selective drug targets, showing several advantages over the active center(s). As a matter of fact, since allosteric binding sites could be faced to a higher evolutionary pressure than active center(s), the use of drugs as allosteric effectors should foresee a decreased potential toxic effects, as “allosteric” drugs could be administrated at a lower dosage (i.e., in a sub-stoichiometric ratio) than drugs targeting directly the active center(s). Another type of pharmacological selectivity that is unique to allosteric modulators is based on cooperativity. Indeed, an allosteric modulator may display cooperativity by binding to a single member of a protein family, without affecting the cooperativity of other members. Lastly, an allosteric modulator, not possessing apparent efficacy, may selectively tune up or down tissue responses in the presence of the endogenous agonist or antagonist, respectively.

Allostery modulation has been identified more and more frequently in the last few years and the number of documented allosteric proteins has been quickly rising. A range of examples illustrating mechanisms of protein allostery are reported here focusing on drugs and related compounds acting as allosteric effectors. The general and widespread features observed in this rapidly growing class of proteins seems to confirm the old forecast by Monod in the early 60’s that “ Allostery is the second secret of life”.

Prof. Dr. Paolo Ascenzi
Prof. Dr. Massimo Coletta
Guest Editors

Published Papers (7 papers)