Chapter 8. Activation mechanisms of chemokine receptors.

Chemokine receptors belong to the large family of 7-transmembrane (7TM) G-protein-coupled receptors. These receptors are targeted and activated by a variety of different ligands, indicating that activation is a result of similar molecular mechanisms but not necessarily similar modes of ligand binding. Attempts to unravel the activation mechanism of 7TM receptors have led to the conclusion that activation involves movements of the transmembrane segments VI and VII in particular, as recently gathered in the Global Toggle Switch Model. However, to understand the activation mechanism completely, more research has to be done in this field. Chemokine receptors are interesting tools in this matter. First, the chemokine system has a high degree of promiscuity that allows several chemokines to target one receptor in different ways, as well as a single chemokine ligand to target several receptors in different ways. Second, the endogenous ligands are large proteins that mainly activate their cognate receptors by interacting with various extracellular-located receptor regions. It is, however, also possible to introduce agonism of simple ligands like metal ions. Thus, the chemokine system offers the possibility to test and compare the activation profiles of several chemically diverse ligands. This also brings up the interesting discussion of allosterism, because small molecules in the chemokine field often interact with allosteric receptor sites.