Structure of the Gq-coupled adhesion receptor ADGRL4
Qingchao Chen1, Anastasiia Gusach1, Aurora Diamante2
1MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, UK.
Nature Communications
|December 30, 2025
Summary
Adhesion G protein-coupled receptors (aGPCRs), like ADGRL4, are crucial in cancer. This study reveals ADGRL4 weakly couples to the Gq protein, offering new therapeutic targets for intractable cancers.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Adhesion G protein-coupled receptors (aGPCRs) are vital for diverse cellular functions, including cancer biology.
- ADGRL4 is upregulated in tumors and implicated in pathogenesis, presenting a potential therapeutic target for cancers like glioblastoma.
Purpose of the Study:
- To investigate the G protein coupling and structure of ADGRL4.
- To understand ADGRL4's signaling mechanisms for potential cancer therapies.
Main Methods:
- Sensitive bioluminescent assay to detect G protein coupling.
- Cryo-electron microscopy (cryo-EM) to determine the structure of ADGRL4-Gq complex.
Main Results:
- ADGRL4 exhibits weak coupling to the Gq protein, with no significant coupling to other G proteins or beta-arrestin.
- The 3.1 Å cryo-EM structure reveals ADGRL4's fold is similar to other aGPCRs, but with distinct, fewer interactions with Gq.
- The structure supports activation of ADGRL4 by its tethered agonist.
Conclusions:
- ADGRL4's weak Gq coupling is a novel finding with implications for its function in cancer.
- The determined structure provides a foundation for developing targeted inhibitors against ADGRL4 in various tumor types.
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