Les récepteurs couplés aux protéines G

Abstract

Fifty years ago, the first successful isolation of enzymes and the study of their reaction mechanisms challenged biochemists to investigate their biological regulation. Various models have been proposed on the basis of available catalytical, pharmacological and structural information. The "allosteric model" of Monod, Wyman and Changeux describes regulatory proteins that can adopt multiple interconvertible conformations, differently stabilized by substrates, products and allosteric effectors. These effectors target regulatory sites topographically distinct from the enzymatic reaction center. Each conformational state is characterized by a unique set of pharmacological, functional and structural properties. The oligomeric nature of the proteins which were used to construct this model allowed to describe an important phenomenon, referred to as cooperativity. It explains how the binding of a molecule to one subunit of the protein can facilitate, or conversely impede, the binding of a second molecule to a neighboring subunit. This concept has evolved and now extends to allosteric regulatory phenomena dealing with distinct effectors that bind to their own sites on a monomeric protein, such as a G-protein coupled receptor. This article focuses on G-protein-coupled receptors and aims to discuss (1) how their functional architecture meets the rules of allostery, and (2) how allosteric effectors (small molecules or cell components), with which the receptors establish stable or transient interactions, may cooperate to finely tune their pharmacological and functional properties.