Chinese scientists successfully resolve glucagon receptor structure

On January 10, the B-type G protein-coupled receptors (GPCRs) play an important role in the body's hormonal homeostasis, and it is also an important therapeutic target for many types of diseases, such as metabolic diseases such as type 2 diabetes. These receptors include the extracellular domain (ECD) and the transmembrane domain (TMD), both of which require interaction with their cognate polypeptide ligands to regulate downstream signaling, which is difficult for researchers to prepare today. High-quality proteins, so it is still a challenge for scientists to determine the full-length structure of class B GPCRs, which also limits the researchers' understanding of the molecular mechanisms of receptor action.

Activation of the human glucagon receptor (GCGR) by the endogenous ligand glucagon can induce the body to release glucose from the liver during fasting, which may serve as a potential therapeutic target for type 2 diabetes; last year Researchers from the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, have determined the full-length crystal structure of GCGR bound to the negative allosteric modulator NNC0640 and the inhibitory antibody mAb1, thus revealing the class B G protein for the first time under high-resolution conditions. A full-length, clear image of the coupled receptor.

Recently, in a research report published in the international journal Nature, researchers from the Shanghai Institute of Materia Medica confirmed the crystal structure of GCGR together with glucagon analog and partial agonist NNC1702. The crystal structure was first demonstrated. Class B G-protein coupled receptors bind to the molecular details of their peptide ligands at high resolution, and the researchers have unexpectedly discovered structurally complex properties that control receptor activation, thereby extending the class B G protein pair. Understanding of the receptor signal transduction process.

This study also provides some clues for researchers to understand the activation mechanism of GCGR. The most discovered finding by researchers is that in the peptide-bound GCGR structure, the receptor is connected to the previously identified non-peptide binding structure. The ECD and TMD linker region (stalk region) and the first extracellular loop can undergo significant conformational changes in the secondary structure, which may be a significant change in the relative orientation between the receptor's ECD and TMD. Binding of peptides and activation of receptors.

In addition, the stalk structure may also regulate receptor activity by promoting conformational movement of the receptor TMD. Researcher ZHAO Qiang said that in this study we observed how the stalk region plays a key role in regulating receptor function. Although it contains only 12 amino acid sequences, which was not found in previous GPCR structural studies, this may be expected to help us promote understanding of the signaling mechanisms of class B G protein-coupled receptors.

Based on the structure of the GCGR-NNC1702 complex, researchers can use a variety of techniques to perform a series of functional studies, such as competitive ligand binding, cell signal transduction, molecular dynamics simulation, and two-electron resonance spectroscopy. It is also possible to determine the structure of the GCGR again, and at the same time confirm the mechanism of conformational change of the receptor under different functional states. Finally, the researchers say that the structure of the new GCGR may provide us with the most accurate template to help develop drugs that target GCGR, thus providing new ideas and hopes for the development of new drugs or therapies for effective treatment of type 2 diabetes.