Determining the structural features of the signaling by the thrombopoietin receptor and of its modulation by small molecule
The thrombopoietin receptor (TpoR) is a type 1 cytokine receptor that regulates, in part, the production of platelets in response to its ligand thrombopoietin. The single transmembrane (TM) domain is thought to be involved in the process of receptor dimerization and activation, but its exact role is poorly defined. We have recently shown that the TM region of TpoR dimerizes strongly and can adopt three different stable, rotationally related conformations involving distinct sets of TM residues, which may correspond to specific states of the full-length receptor (active, inactive and partially active). We have also proposed a novel allosteric mechanism of action for a small molecule TpoR agonist that does not mimic the natural ligand: the equilibrium existing between the inactive and active states allows the binding of the small drug-like compound to an essential TM histidine (which is exposed in the active state), leading to a shift of the equilibrium toward the active state and consequently, to signaling (see figure). However, several important questions remain to be answered to obtain a clearer understanding of TpoR dynamics and modulation of cytokine receptor by small molecules.