Structures of the ADGRG2-G_s complex in apo and ligand-bound forms

Area of Science:

• Structural Biology
• Membrane Receptor Signaling
• Endocrinology

Background:

• Adhesion G protein-coupled receptors (ADGRs) lack detailed structural and ligand information.
• ADGRG2 is crucial for male fertility, but its activation and signaling pathways remain poorly understood.
• Understanding ADGRG2 is vital for reproductive health research.

Purpose of the Study:

• To determine the cryo-electron microscopy (cryo-EM) structure of ADGRG2 in complex with a Gs trimer.
• To identify potential ligands that bind to ADGRG2.
• To provide a structural basis for ADGRG2 activation and signaling.

Main Methods:

• Cryogenic-electron microscopy (cryo-EM) was employed to solve the structure of apo-ADGRG2-Gs complex.
• Structural analysis identified key features determining the active state of ADGRG2.
• Ligand screening was performed to identify molecules binding to ADGRG2.

Main Results:

• The cryo-EM structure of apo-ADGRG2-Gs revealed two kinks critical for receptor activation.
• A potential ligand-binding pocket was identified in ADGRG2.
• Dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate, and deoxycorticosterone were identified as potential ADGRG2 ligands, with structural details of DHEA binding elucidated.

Conclusions:

• The study provides the first structural insights into ADGRG2 activation and signaling.
• Steroid hormones, including DHEA, are characterized as novel ligands for ADGRG2.
• These findings offer valuable tools for future functional investigations of the orphan ADGRG2 receptor.