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, a 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) under Chinese Academy of Sciences made progresses in discovering a common mechanism for activation of class B GPCRs through studying ligand-independent activation of GPCR. The finding has been published in the Journal of Biological Chemistry (JBC) and further been chosen for the cover issue.

Researchers at SIMM, CAS use the glucagon receptor (GCGR), an extensively studied class B GPCR as a model for understanding 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).

The research 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. The study found this activation mechanism 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 finding suggests the activation mechanism of conformation changes about TM6 , previously reported only in class A GPCRs, could be extended to class B GPCRs. This research 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

Full text link:http://www.jbc.org/content/292/24/9865
The cover figure link：http://www.jbc.org/content/292/24.cover-expansion

The cover figure of JBC (Image prepared by YIN Yanting)

Corresponding authors:
H. Eric Xu
Email： Eric.Xu@vai.org
WANG Ming-Wei
Email： mwwang@simm.ac.cn