GPR17 structure and agonism with small molecules and oxysterols

Area of Science:

• Neuroscience
• Pharmacology
• Structural Biology

Background:

• G protein-coupled receptor 17 (GPR17) is a key regulator of central nervous system myelination.
• Inhibiting GPR17 presents a therapeutic strategy for promoting remyelination.
• Understanding GPR17's structural basis for ligand binding is crucial for drug discovery.

Purpose of the Study:

• To determine the structural basis of GPR17 agonism and antagonism.
• To inform rational drug discovery for GPR17-targeted therapies.

Main Methods:

• Cryo-electron microscopy (cryo-EM) to obtain novel GPR17 structures.
• Biophysical and cellular characterization of ligand binding and function.
• Pharmacological and photoaffinity labeling studies.

Main Results:

• Novel cryo-EM structures revealed GPR17 bound to orthosteric antagonists or agonists complexed with G proteins.
• Both orthosteric ligands bind to the lateral edge of a restricted pocket, limited by an elongated extracellular loop 2.
• Endogenous oxysterol agonists were found to bind allosterically, distinct from orthosteric ligands.

Conclusions:

• The orthosteric binding site of GPR17 is structurally constrained, limiting the development of potent orthosteric ligands.
• Allosteric targeting of GPR17 represents a promising alternative strategy for developing antagonists.
• These findings provide critical insights for advancing GPR17-based therapeutic approaches for neurological disorders.