Crystal structure and functional characterization of the GPR17 receptor, a novel pharmacological target for remyelination therapy in multiple sclerosis

Background: The reconstitution of a functional myelin sheath in the central nervous system (CNS) is the cornerstone for the functional recovery in multiple sclerosis (MS) patients. Recent findings demonstrated that agonist compounds of the class-A G-protein coupled receptor GPR17 can promote the activity of oligodendrocyte precursor cells (OPCs) towards CNS remyelination. The development of agonist compounds targeting GPR17 to promote myelination in the CNS requires the availability of detailed structural and functional information on GPR17. Goal: Initially, we engineered protein variants that can be expressed and purified for subsequent crystallization. Secondly, we assayed the pharmacological profile of such constructs both through in vitro functional assays and Transformed Infrared spectroscopy. Moreover, via molecular modelling, we characterized in silico the structure of GPR17 and its interactions with new high-affinity GPR17 ligands that will represent new leads for remyelinating compounds. We will also investigate how specific molecules can activate both GPR17 and CXCRs. The detailed understanding of GPR17::CXCRs cross-talk with respect to ligand recognition, signal transduction, and oligomerization properties will allow to deploy different pharmacological strategies aimed at controlling receptor dysregulation through identification of new promiscuous ligands.