Exploring and exploiting allostery: Models, evolution, and drug targeting

The concept of allostery was elaborated almost 50 years ago by Monod and coworkers to provide a framework for interpreting experimental studies on the regulation of protein function. In essence, binding of a ligand at an allosteric site affects the function at a distant site exploiting protein flexibility and reshaping protein energy landscape. Both monomeric and oligomeric proteins can be allosteric. In the past decades, the behavior of allosteric systems has been analyzed in many investigations while general theoretical models and variations thereof have been steadily proposed to interpret the experimental data. Allostery has been established as a fundamental mechanism of regulation in all organisms, governing a variety of processes that range from metabolic control to receptor function and from ligand transport to cell motility. A number of studies have shed light on how evolutionary pressures have favored and molded the development of allosteric features in specific macromolecular systems. The widespread occurrence of allostery has been recently exploited for the development and design of allosteric drugs that bind to either physiological or non-physiological allosteric sites leading to gain of function or loss of function. This article is part of a Special Issue entitled: Protein Dynamics: Experimental and Computational Approaches.

Research Highlights
► The concept of allostery provides a general framework for understanding the regulation of protein function.
► Both in monomeric and oligomeric proteins, ligand binding at an allosteric site affects the function at a distant site exploiting the conformational flexibility and reshaping the energy landscape.
► Evolutionary pressures have favored and molded the development of allostery.
► The widespread occurrence of protein allostery is being exploited for the development and design of allosteric drugs.