Class B G protein-coupled receptors (GPCRs) of the secretin family are important drug targets in many human diseases, such as diabetes, neurodegeneration, cardiovascular disease and psychiatric disorders. However, so far, the mechanistic understanding of how these class B GPCRs are activated by the peptide hormone and the detailed conformational changes remains unknown.

Scientists from Shanghai Institute of Materia Medica (SIMM) of Chinese Academy of Sciences made progress in discovering a common mechanism for activation of class B GPCRs through studying ligand-independent activation of GPCR. This study was published in Journal of Biological Chemistry  and was chosen as the cover issue.

Researchers used the glucagon receptor (GCGR), an extensively studied class B GPCR as a model, to understand the activation mechanism. GCGR was an active therapeutic target for treatment of type II diabetes and clinical obesity as it can stimulate both glycogenolysis and gluconeogenesis to maintain normal blood glucose levels once activated by the glucagon (GCG).

They revealed how the hydrophobic lock and polar core formed in one of the transmembrane segments (TM6) of GCGR allows for the protein’s responsive activation. This activation mechanism was found to be present in other members of class B GPCRs including parathyroid hormone 1 receptor (PTH1R), pituitary adenylate cyclase-activating polypeptide type 1 receptor (PAC1R), vasoactive intestinal peptide receptor1 (VIP1R), and corticotropin-releasing factor receptor type 1 (CRF1R).

This study suggested the activation mechanism of conformation changes about TM6, previously reported only in class A GPCRs, could be extended to class B GPCRs. It could benefit rational design of small-molecule modulator in developing drugs to target class B GPCRs.

This work was supported by National Natural Science Foundation of China Grant, Ministry of Science and Technology of China Grants, National Institutes of Health Grants and Shanghai Science and Technology Development Fund Grants.

Figure: The cover figure of JBC (Image by YIN Yanting)