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GPR174 Antagonism: Structure, Function, and Dynamics.

Vijay Kumar Bhardwaj, Alemayehu Gorfe

Biorxiv : the Preprint Server for Biology

|September 26, 2025

Summary

This summary is machine-generated.

GPR174, a receptor implicated in cancer immunotherapy resistance, is inactivated by the antagonist mPS, unlike its activator lysophosphatidylserine (LysoPS). This provides a basis for developing new cancer therapies.

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Area of Science:

Immunology
Pharmacology
Structural Biology

Background:

GPR174 is an immune-restricted G-protein-coupled receptor (GPCR) activated by lysophosphatidylserine (LysoPS).
Elevated LysoPS in tumors can lead to immunosuppression and resistance to cancer immunotherapies.
Understanding GPR174's interaction with ligands is crucial for developing targeted cancer treatments.

Purpose of the Study:

To investigate the molecular mechanisms underlying GPR174 activation and antagonism.
To compare the binding modes and conformational dynamics of GPR174 with its activator (LysoPS) and an antagonist (mPS).
To provide a structural basis for designing novel GPR174-targeted cancer immunotherapies.

Main Methods:

Molecular modeling of GPR174 bound to mPS.
Extensive molecular dynamics (MD) simulations in a heterogeneous lipid bilayer.
Parallel simulations of LysoPS-bound GPR174.
Network analysis and protein-lipid interaction analysis.

Main Results:

mPS binding inactivated GPR174, reducing conformational dynamics and stabilizing interactions with transmembrane helix 1.
LysoPS binding induced greater conformational flexibility, multiple binding poses, and transient membrane interactions.
LysoPS engaged conserved activation motifs (PIF, DRY, N/DPxxY) to couple ligand binding to the G-protein interface, while mPS disrupted these pathways.
Membrane lipids like PIP2 were shown to modulate ligand dynamics and receptor conformational states.

Conclusions:

Distinct ligand-specific mechanisms govern GPR174 modulation by LysoPS and mPS.
mPS acts as an effective antagonist by disrupting key activation pathways within GPR174.
These findings offer a framework for the rational design of selective GPR174 antagonists for cancer immunotherapy.