Ligand entry pathways control the chemical space recognized by GPR183.

Area of Science:

• Structural Biology
• Pharmacology
• Immunology

Background:

• G protein-coupled receptor (GPCR) GPR183 plays a key role in immune function and disease.
• GPR183 exhibits ligand promiscuity, binding diverse molecules like oxysterols and synthetic compounds.
• Understanding GPR183's ligand recognition mechanisms is crucial for therapeutic development.

Purpose of the Study:

• To elucidate the structural basis of GPR183's ligand promiscuity.
• To identify and characterize the ligand entry pathways into GPR183.
• To provide insights into GPCR ligand binding mechanisms.

Main Methods:

• Molecular dynamics simulations with enhanced sampling techniques.
• Cell-based validation experiments using GPR183 mutants.
• In vitro binding and signaling assays.

Main Results:

• Identified two distinct ligand entry channels: a lateral membrane channel and an extracellular polar channel.
• Developed a detailed structural model for the endogenous ligand 7α,25-OHC entry via the lateral channel.
• Experimental data confirmed the functional importance of the lateral channel for ligand binding and signaling.

Conclusions:

• GPR183 utilizes multiple entry pathways to accommodate diverse ligands.
• The findings offer a generalizable mechanism for GPCR ligand entry and recognition.
• This research has significant implications for designing novel therapeutics targeting GPR183.